Inhibitors of c-fms kinase

ABSTRACT

The invention is directed to compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein Z, X, J, R 2  and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget&#39;s disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application Ser.Nos. 60/793,697, filed on Apr. 20, 2006, and 60/883,539, filed Jan. 5,2007, the contents of both of which are hereby incorporated by referencein their entirety.

BACKGROUND OF THE INVENTION

The invention relates to novel compounds that function as proteintyrosine kinase inhibitors. More particularly, the invention relates tonovel compounds that function as inhibitors of c-fms kinase.

Protein kinases are enzymes that serve as key components of signaltransduction pathways by catalyzing the transfer of the terminalphosphate from adenosine 5′-triphosphate (ATP) to the hydroxy group oftyrosine, serine and threonine residues of proteins. As a consequence,protein kinase inhibitors and substrates are valuable tools forassessing the physiological consequences of protein kinase activation.The overexpression or inappropriate expression of normal or mutantprotein kinases in mammals has been demonstrated to play significantroles in the development of many diseases, including cancer anddiabetes.

Protein kinases can be divided into two classes: those whichpreferentially phosphorylate tyrosine residues (protein tyrosinekinases) and those which preferentially phosphorylate serine and/orthreonine residues (protein serine/threonine kinases). Protein tyrosinekinases perform diverse functions ranging from stimulation of cellgrowth and differentiation to arrest of cell proliferation. They can beclassified as either receptor protein tyrosine kinases or intracellularprotein tyrosine kinases. The receptor protein tyrosine kinases, whichpossess an extracellular ligand binding domain and an intracellularcatalytic domain with intrinsic tyrosine kinase activity, aredistributed among 20 subfamilies.

Receptor tyrosine kinases of the epidermal growth factor (“EGF”) family,which includes HER-1, HER-2/neu and HER-3 receptors, contain anextracellular binding domain, a transmembrane domain and anintracellular cytoplasmic catalytic domain. Receptor binding leads tothe initiation of multiple intracellular tyrosine kinase dependentphosphorylation processes, which ultimately results in oncogenetranscription. Breast, colorectal and prostate cancers have been linkedto this family of receptors.

Insulin receptor (“IR”) and insulin-like growth factor I receptor(“IGF-1R”) are structurally and functionally related but exert distinctbiological effects. IGF-1R overexpression has been associated withbreast cancer.

Platelet derived growth factor (“PDGF”) receptors mediate cellularresponses that include proliferation, migration and survival and includePDGFR, the stem cell factor receptor (c-kit) and c-fms. These receptorshave been linked to diseases such as atherosclerosis, fibrosis andproliferative vitreoretinopathy.

Fibroblast growth factor (“FGR”) receptors consist of four receptorswhich are responsible for the production of blood vessels, for limboutgrowth, and for the growth and differentiation of numerous celltypes.

Vascular endothelial growth factor (“VEGF”), a potent mitogen ofendothelial cells, is produced in elevated amounts by many tumors,including ovarian carcinomas. The known receptors for VEGF aredesignated as VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4). A relatedgroup of receptors, tie-1 and tie-2 kinases, have been identified invascular endothelium and hematopoietic cells. VEGF receptors have beenlinked to vasculogenesis and angiogenesis.

Intracellular protein tyrosine kinases are also known as non-receptorprotein tyrosine kinases. Over 24 such kinases have been identified andhave been classified into 11 subfamilies. The serine/threonine proteinkinases, like the cellular protein tyrosine kinases, are predominantlyintracellular.

Diabetes, angiogenesis, psoriasis, restenosis, ocular diseases,schizophrenia, rheumatoid arthritis, cardiovascular disease and cancerare exemplary of pathogenic conditions that have been linked withabnormal protein tyrosine kinase activity. Thus, a need exists forselective and potent small-molecule protein tyrosine kinase inhibitors.U.S. Pat. Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and PCTInternational Applications WO 01/47897, WO 00/27820 and WO 02/068406 areindicative of recent attempts to synthesize such inhibitors.

SUMMARY OF THE INVENTION

The invention addresses the current need for selective and potentprotein tyrosine kinase inhibitors by providing potent inhibitors ofc-fms kinase. The invention is directed to the novel compounds ofFormula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:

-   W is

-   wherein R⁴=H, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, —C₍₁₋₃₎alkyl, —CO₂R⁵,    CONR⁶R⁷, C≡CR⁸, or CN;    -   wherein R⁵=H, or —C₍₁₋₃₎alkyl;        -   R⁶=H, or —C₍₁₋₃₎alkyl;        -   R⁷=H, or —C₍₁₋₃₎alkyl; and        -   R⁸=H, —CH₂OH, or —CH₂CH₂OH;-   R² is cycloalkyl (including cyclohexenyl, and cycloheptenyl),    spiro-substituted cycloalkenyl (including spiro[2.5]oct-5-enyl,    spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl, and    spiro[5.5]undec-2-enyl)heterocyclyl (including piperidinyl),    spirosubstituted piperidinyl (including 3-aza-spiro[5.5]undecanyl,    and 8-aza-spiro[4.5]decanyl), thiophenyl, dihydrosulfonopyranyl,    phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which    may be independently substituted with one or two of each of the    following: chloro, fluoro, hydroxy C₍₁₋₃₎alkyl, and C₍₁₋₄₎alkyl    (said substituted cycloalkyls include 4,4-dimethyl cyclohexenyl,    4,4-diethyl cyclohexenyl, 4-methyl cyclohexenyl, 4-ethyl    cyclohexenyl, 4-n-propyl cyclohexenyl, 4-iso-propyl cyclohexenyl,    and 4-tert-butyl cyclohexenyl; said substituted piperidinyls include    4-methyl piperidinyl, 4-ethyl piperidinyl,    4-(1′hydroxyeth-2′yl)piperidinyl, and 4,4 dimethyl piperidinyl);-   X is selected from the group consisting of:

-   wherein R¹ and R¹⁰ are independently is H, —CH₃, or —C₂ to C₅ alkyl    optionally substituted with 1 or 2 of: Me, Et, OH, NH₂, NHMe, NMe₂,    NHEt, NEt₂, pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH and    such that when any two heteroatoms are attached to said C₂ to C₅    alkyl group there exists at least two carbon atoms between them, and-   R³ is —SO₂Me, SO₂Et, —CO₂R⁹, —NO₂, or —CN;    -   wherein R⁹=H, or C₍₁₋₃₎alkyl;-   Z is H, F, Cl, Br, C₁-C₃ alkyl or —CH₂OH; and-   J is CH or N.

Herein and throughout this application, the terms “Me”, “Et”, “Pr”, and“Bu” refer to methyl, ethyl, propyl, and butyl respectively.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to the novel compounds of Formula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:

-   W is

-   wherein R⁴=H, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, —C₍₁₋₃₎alkyl, —CO₂R⁵,    CONR⁶R⁷, C≡CR⁸, or CN;    -   wherein R⁵=H, or —C₍₁₋₃₎alkyl;        -   R⁶=H, or —C₍₁₋₃₎alkyl;        -   R⁷=H, or —C₍₁₋₃₎alkyl; and        -   R⁸=H, —CH₂OH, or —CH₂CH₂OH;-   R² is cycloalkyl (including cyclohexenyl, and cycloheptenyl),    spiro-substituted cycloalkenyl (including spiro[2.5]oct-5-ene,    spiro[3.5]non-6-ene, spiro[4.5]dec-7-ene, and    spiro[5.5]undec-2-ene)heterocyclyl (including piperidinyl),    spirosubstituted piperidinyl (including 3-aza-spiro[5.5]undecane,    and 8-aza-spiro[4.5]decane), thiophenyl, dihydrosulfonopyranyl,    phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which    may be independently substituted with one or two of each of the    following: chloro, fluoro, hydroxy C₍₁₋₃₎alkyl, and C₍₁₋₄₎alkyl    (said substituted cycloalkyls include 4,4-dimethyl cyclohexenyl,    4,4-diethyl cyclohexenyl, 4-methyl cyclohexenyl, 4-ethyl    cyclohexenyl, 4-n-propyl cyclohexenyl, 4-iso-propyl cyclohexenyl,    and 4-tert-butyl cyclohexenyl; said substituted piperidinyls include    4-methyl piperidinyl, 4-ethyl piperidinyl,    4-(1′hydroxyeth-2′yl)piperidinyl, and 4,4 dimethyl piperidinyl);-   X is selected from the group consisting of:

-   wherein R¹ and R¹⁰ are independently H, —CH₃, or —C₂ to C₅ alkyl    optionally substituted with one or two of: Me, Et, OH, NH₂, NHMe,    NMe₂, NHEt, NEt₂, pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH    and such that when any two heteroatoms are attached to said C₂ to C₅    alkyl group there exists at least two carbon atoms between them, and-   R³ is —SO₂Me, SO₂Et, —CO₂R⁹, —NO₂, or —CN;    -   wherein R⁹=H, or C₍₁₋₃₎alkyl;-   Z is H, F, Cl, Br, C₁-C₃ alkyl or —CH₂OH; and-   J is CH or N.

In a preferred embodiment of the invention:

-   W is

-   R² is

-   X is selected from the group consisting of:

-   wherein R¹ and R¹⁰ are independently H, —CH₃, or —C₂ to C₅ alkyl    optionally substituted with 1 or 2 of: Me, Et, OH, NH₂, NHMe, NMe₂,    NHEt, NEt₂, pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH and    such that when any two heteroatoms are attached to said C₂ to C₅    alkyl group there exists at least two carbon atoms between them, and-   R³ is —SO₂Me, SO₂Et, —CO₂R⁹, —NO₂, or —CN;    -   wherein R⁹=H, or C₍₁₋₃₎alkyl;-   Z is H, F, Cl, Br, C₁-C₃ alkyl or —CH₂OH; and-   J is CH or N;    as well as solvates, hydrates, tautomers and pharmaceutically    acceptable salts thereof.

In another embodiment of the invention:

-   W is

-   R² is

-   X is selected from the group consisting of:

-   wherein R¹ is H, —CH₃, or —C₂ to C₅ alkyl optionally substituted    with one or two of: Me, Et, OH, NH₂, NHMe, NMe₂, NHEt, NEt₂,    pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH and such that when    any two heteroatoms are attached to said C₂ to C₅ alkyl group there    exists at least two carbon atoms between them, and-   R³ is —SO₂Me, SO₂Et, —CO₂R⁹, —NO₂, or —CN;    -   wherein R⁹=H, or C₍₁₋₃₎alkyl;-   Z is H, C₁-C₃ alkyl or —CH₂OH; and-   J is CH or N;    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

In another embodiment of the invention:

-   W is

-   R² is

-   Z is H, or —CH₂OH;-   J is CH;-   X is selected from the group consisting of

-   wherein R¹ is H, —CH₂CH₃, —CH₂CH₂OH, or —CH₃; and-   R³ is —SO₂CH₃, —CO₂CH₃, —NO₂, or —CN;    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

In another embodiment of the invention:

-   W is

-   R² is

-   Z is H, or —CH₂OH;-   J is CH;-   X is selected from the group consisting of

-   wherein R¹ is H, or —CH₃; and-   R³ is —SO₂CH₃, or —CN;    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

An embodiment of the invention is compounds selected from the groupconsisting of the compounds of Examples 1 and 3 to 53, solvates,hydrates, tautomers and pharmaceutically acceptable salts of thesecompounds, and any combination thereof.

Still another embodiment is compounds selected from the group consistingof:

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof. The compounds of this embodiment are in Examples 1-15.

Yet another embodiment is a compound selected from the group consistingof:

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof. The compounds of this embodiment are in Examples 3, 8, 9, and11.

Another embodiment is the compound

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof. The compound of this embodiment is Example 54.

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I. A preferredtyrosine kinase is c-fms.

The invention is considered to include the enantiomeric, diastereomericand tautomeric forms of all compounds of Formula I as well as theirracemic mixtures. In addition, some of the compounds represented byFormula I may be prodrugs, i.e., derivatives of an acting drug thatpossess superior delivery capabilities and therapeutic value as comparedto the acting drug. Prodrugs are transformed into active drugs by invivo enzymatic or chemical processes.

DEFINITIONS

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwiseindicated, and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl.

The term “hydroxyalkyl” refers to both linear and branched chainradicals of up to 6 carbon atoms, in which one hydrogen atom has beenreplaced with an OH group.

The term “hydroxyalkylamino” refers to an hydroxyalkyl group in whichone hydrogen atom from the carbon chain has been replaced with an aminogroup, wherein the nitrogen is the point of attachment to the rest ofthe molecule.

The term “cycloalkyl” refers to a saturated or partially unsaturatedring composed of from 3 to 8 carbon atoms. Up to four alkyl substituentsmay optionally be present on the ring. Examples include cyclopropyl,1,1-dimethyl cyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl,cyclopentenyl, cyclohexenyl, and 4,4-dimethyl cyclohexenyl.

The term “aminoalkyl” refers to at least one primary or secondary aminogroup bonded to any carbon atom along an alkyl chain, wherein an alkylgroup is the point of attachment to the rest of the molecule.

The term “alkylamino” refers to an amino with one alkyl substituent,wherein the amino group is the point of attachment to the rest of themolecule.

The term “dialkylamino” refers to an amino with two alkyl substituents,wherein the amino group is the point of attachment to the rest of themolecule.

The term “heteroaromatic” or “heteroaryl” refers to 5- to 7-memberedmono- or 8- to 10-membered bicyclic aromatic ring systems, any ring ofwhich may consist of from one to four heteroatoms selected from N, O orS where the nitrogen and sulfur atoms can exist in any allowed oxidationstate. Examples include benzimidazolyl, benzothiazolyl, benzothienyl,benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl,thiazolyl and thienyl.

The term “heteroatom” refers to a nitrogen atom, an oxygen atom or asulfur atom wherein the nitrogen and sulfur atoms can exist in anyallowed oxidation states.

The term “alkoxy” refers to straight or branched chain radicals of up to12 carbon atoms, unless otherwise indicated, bonded to an oxygen atom.Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.

The term “aryl” refers to monocyclic or bicyclic aromatic ring systemscontaining from 6 to 12 carbons in the ring. Alkyl substituents mayoptionally be present on the ring. Examples include benzene, biphenyland napththalene.

The term “aralkyl” refers to a C₁₋₆ alkyl group containing an arylsubstituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.

The term “sulfonyl” refers to the group —S(O)₂R_(a), where R_(a) ishydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl. A “sulfonylating agent” adds the —S(O)₂R_(a) group to amolecule.

The term “spiro-substituted cycloalkenyl” refers to a pair of cycloalkylrings that share a single carbon atom and wherein at least one of therings is partially unsaturated, for example:

The term “spiro-substituted heterocyclyl” refers to a heterocyclyl andcycloalkyl ring that share a single carbon atom, for example:

Therapeutic Uses

The compounds of Formula I represent novel potent inhibitors of proteintyrosine kinases, such as c-fms, and may be useful in the prevention andtreatment of disorders resulting from actions of these kinases.

The invention also provides methods of inhibiting a protein tyrosinekinase comprising contacting the protein tyrosine kinase with aneffective inhibitory amount of at least one of the compounds of FormulaI. A preferred tyrosine kinase is c-fms. The compounds of the presentinvention are also inhibitors of FLT3 tyrosine kinase activity. In oneembodiment of inhibiting a protein tyrosine kinase, at least one of thecompounds of Formula I is combined with a known tyrosine kinaseinhibitor.

In various embodiments of the invention, the protein tyrosine kinasesinhibited by the compounds of Formula I are located in cells, in amammal or in vitro. In the case of mammals, which includes humans, atherapeutically effective amount of a pharmaceutically acceptable formof at least one of the compounds of Formula I is administered.

The invention further provides methods of treating cancer in mammals,including humans, by administration of a therapeutically effectiveamount of a pharmaceutically acceptable composition of least onecompound of Formula I. Exemplary cancers include, but are not limitedto, acute myeloid leukemia, acute lymphocytic leukemia, ovarian cancer,uterine cancer, prostate cancer, lung cancer, breast cancer, coloncancer, stomach cancer, and hairy cell leukemia. The invention alsoprovides methods of treating certain precancerous lesions includingmyelofibrosis. In one embodiment of the invention, an effective amountof at least one compound of Formula I is administered in combinationwith an effective amount of a chemotherapeutic agent.

The invention further provides methods of treating and of preventingmetastasis arising from cancers that include, but are not limited to,ovarian cancer, uterine cancer, breast cancer, prostate cancer, lungcancer, colon cancer, stomach cancer, and hairy cell leukemia.

The invention further provides methods for the treatment osteoporosis,Paget's disease, and other diseases in which bone resorption mediatesmorbidity including rheumatoid arthritis and other forms of inflammatoryarthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma,myeloma, and tumor metastasis to bone as occurs frequently in cancersincluding, but not limited to, breast cancer, prostate cancer, and coloncancer.

The invention also provides methods of treating pain, in particularskeletal pain caused by tumor metastasis or osteoarthritis, as well asvisceral, inflammatory, and neurogenic pain.

The invention also provides methods of treating cardiovascular,inflammatory, and autoimmune diseases in mammals, including humans, byadministration of a therapeutically effective amount of apharmaceutically acceptable form of at least one of the compounds ofFormula I. Examples of diseases with an inflammatory component includeglomerulonephritis, inflammatory bowel disease, prosthesis failure,sarcoidosis, congestive obstructive pulmonary disease, idiopathicpulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis,diabetes, tumor related angiogenesis, age-related macular degeneration,diabetic retinopathy, restenosis, schizophrenia or Alzheimer's dementia.These may be effectively treated with compounds of this invention. Otherdiseases that may be effectively treated include, but are not limited toatherosclerosis and cardiac hypertrophy.

Autoimmune diseases such as systemic lupus erythematosus, rheumatoidarthritis and other forms of inflammatory arthritis, psoriasis—Sjogren'ssyndrome, multiple sclerosis, or uveitis, can also be treated withcompounds of this invention.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation, prevention, treatment, orthe delay of the onset or progression of the symptoms of the disease ordisorder being treated.

When employed as protein tyrosine kinase inhibitors, the compounds ofthe invention may be administered in an effective amount within thedosage range of about 0.5 mg to about 10 g, preferably between about 0.5mg to about 5 g, in single or divided daily doses. The dosageadministered will be affected by factors such as the route ofadministration, the health, weight and age of the recipient, thefrequency of the treatment and the presence of concurrent and unrelatedtreatments.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for compounds of the present invention or apharmaceutical composition thereof will vary according to the desiredeffect. Therefore, optimal dosages to be administered may be readilydetermined by one skilled in the art and will vary with the particularcompound used, the mode of administration, the strength of thepreparation, and the advancement of the disease condition. In addition,factors associated with the particular subject being treated, includingsubject age, weight, diet and time of administration, will result in theneed to adjust the dose to an appropriate therapeutic level. The abovedosages are thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

The compounds of Formula I may be formulated into pharmaceuticalcompositions comprising any known pharmaceutically acceptable carriers.Exemplary carriers include, but are not limited to, any suitablesolvents, dispersion media, coatings, antibacterial and antifungalagents and isotonic agents. Exemplary excipients that may also becomponents of the formulation include fillers, binders, disintegratingagents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts which are formed from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, benzoate,benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride,hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate,pivalate, propionate, succinate, sulfate and tartrate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamino salts and salts withamino acids such as arginine. Also, the basic nitrogen-containing groupsmay be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered byany means that accomplish their intended purpose. Examples includeadministration by parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, buccal or ocular routes. Alternatively orconcurrently, administration may be by the oral route. Suitableformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form, for example, water-solublesalts, acidic solutions, alkaline solutions, dextrose-water solutions,isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

The present invention also encompasses a method of making apharmaceutical composition comprising mixing a pharmaceuticallyacceptable carrier with any of the compounds of the present invention.Additionally, the present invention includes pharmaceutical compositionsmade by mixing a pharmaceutically acceptable carrier with any of thecompounds of the present invention. As used herein, the term“composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, the compounds mayform solvates, for example with water (i.e., hydrates) or common organicsolvents. As used herein, the term “solvate” means a physicalassociation of the compounds of the present invention with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scopesolvates of the compounds of the present invention. Thus, in the methodsof treatment of the present invention, the term “administering” shallencompass the means for treating, ameliorating or preventing a syndrome,disorder or disease described herein with the compounds of the presentinvention or a solvate thereof, which would obviously be included withinthe scope of the invention albeit not specifically disclosed.

Methods of Preparation

Scheme 1 describes the synthesis of compounds of Formula I where X is

(Y is CO and SO₂ in Scheme 1).

Commercially available 2-phenyl-propane-1,2-diol can be converted toaminodiol 1-1 where J is CH according to the procedure described inJournal of Medicinal Chemistry 40(25), 4030-4052, (1997). It isunderstood that when J is N, a similar procedure may be used, startingfrom (2-pyridyl)propane diol (Tetrahedron: Asymmetry 8(13), 2175-2187,(1997)).

Conversion of aminodiol 1-1 to compound 1-2 is accomplished usingstandard protecting group chemistry. The examples of suitableN-protecting groups P¹ can be found in “Protective Groups in OrganicSynthesis,” by Theodora W. Greene and Peter G. M. Wuts, John Wiley &Sons. Inc, NY, (1999). The preferred protecting group istert-butyloxycarbonyl (BOC) which can be introduced by reactingaminodiol 1-1 with di-tert-butyldicarbonate ((BOC)₂O) in tetrahydrofuran(THF) and aq Na₂CO₃. The conversion of diol 1-2 to diamine 1-5 can beaccomplished via the corresponding diazide 1-4 which can be prepared bythe displacement of leaving groups L¹ of intermediate 1-3 with azideanion and reduction to diamine 1-5 with known methods such as Ph₃P orpreferably catalytic hydrogenation. Examples of suitable leaving groupsL¹ are mesylates, tosylates, triflates and halogens such as Br or I. TheL¹ in intermediate 1-3 can be introduced by conversion of the diolfunction of intermediate 1-2 using known literature methods. Thepreferable leaving group is mesylate which can be prepared by thereaction of diol 1-2 with mesylchloride (MsCl) and a tertiary aminebases such as triethylamine (Et₃N) in DCM. Alternatively, intermediate1-2 can be converted to 1-5 in one step utilizing known syntheticprotocols such as Ph₃P/NaN₃ (Synthetic Communications 30(12), 2233,(2000)) or suitable modification of such protocols.

The transformation of diamine 1-5 to cyclic urea 1-6 (where Y is CO) canbe performed by reaction of diamine with carbonylating agents (“phosgeneequivalents”) such S,S-dimethyldithiocarbonate (DMDTC) (J. Org. Chem.,61, 4175, (1996)), bis(4-nitrophenyl)carbonate (Helvetica Chimica Acta82(8), 1195, (1999)), urea (J. Chem. Soc., Perkin Trans 2, 317, (1981)),benzyl succinimidocarbonate (Bull. Chem. Soc., Jpn., 71, 699, (1998)),hexachloroacetone (Liebigs Annalen/Recueil, (5), 925, (1997)),triphosgene (Tett. Lett., 32, 4185, (1991)) and carbodiimdazole (J. Med.Chem., 40, 1707, (1997)) at appropriate temperatures and solvents orusing complexes of transition metals such as tungsten (J. Org. Chem.,67, 4086, (2002)), Ni (J. Organomet. Chem., 419, 251, (1991)), Pd(Macromolecules, 26, 1784, (1993)), Ru (J. Mol. Catal. A: Chem., 122,103, (1997)), Mn (Inorg. Chem. 4, 293, (1965,) and J. Organomet. Chem.,134, 203, (1977)) or Co (J. Mol. Catal., 60, 41, (1990)). The main groupelements such as S (J. Org. Chem. 26, 3306 and 3309, (1961,)) and Se(Bull. Chem. Soc., Jpn., 60, 1793, (1987)) can also be used to catalyzethis transformation.

The preferred method of cyclic urea 1-6 (Y is CO) synthesis is thereaction of diamine 1-5 with bis(4-nitrophenyl)carbonate in1,2-dichloroethane. The sulfonyl urea 1-6 (Y is SO₂) can be produced inanalogous fashion by replacing the carbonylating agent withsulfonylating agents such as sulfuryl chloride (Acta. Chem. Scand, 17,2141, (1963)) and sulfamide (Bioorganic and Medicinal Chemistry, 13,755, (2005)). Thus, a reaction of diamine 1-5 with sulfamide in pyridinecan be used to produce the sulfonylurea 1-6.

Sulfonylureas and ureas 1-6 can be N-alkylated using known literatureprocedures (Synthetic Communications, 18(5), 487-494 (1988)), WO9600708, DE 4028040). The preferred methods of alkylation include, butare not limited to, thermal reaction with alkylating agents, such asalkyl halides R¹L² (L² is halogen) and sulfates (R¹OSO₂OR¹) in thepresence of a suitable phase-transfer catalyst such astetrabutylammonium salts, in solvents such as toluene and dioxane toproduce intermediate 1-8 where Y is CO, or SO₂, and R¹ is alkyl.

The protecting group P¹ of intermediate 1-8 (where Y is CO, SO₂) can beremoved under appropriate conditions to unmask the amine function. Forthe removal of a BOC group in intermediate 1-8 (where Y is CO, SO₂), TFAcan be used and the resulting aniline can be isolated as its TFA salt orfree base.

The compounds of Formula 1-10, where Y is CO or SO₂, can be obtained byortho-halogenation, preferably bromination, of the deprotected aminocompound, followed by metal-catalyzed coupling reactions of bromoaminointermediate 1-9 with boronic acids or boronate esters (Suzukireactions, where R²M¹ is R²B(OH)₂ or a boronic ester) or tin reagents(Stille reactions, where R²M¹ is R²Sn(alkyl)₃) (for reviews, see N.Miyaura, A. Suzuki, Chem. Rev., 95:2457 (1995), J. K. Stille, Angew.Chem., Int. Ed. Engl., 25: 508024 (1986) and A. Suzuki inMetal-Catalyzed Coupling Reactions, F. Deiderich, P. Stang, Eds.,Wiley-VCH, Weinheim (1988)). Similarly, the BOC protected intermediate1-6 can be ortho-halogenated to obtain intermediate 1-7 which can thenbe deprotected under acidic condition to produce intermediate 1-9 whereR¹ is H, and Y is CO or SO₂.

The preferred conditions for the above bromination areN-bromosuccinimide (NBS) in a suitable solvent such asN,N-dimethylformamide (DMF), dichloromethane (DCM) or preferablyacetonitrile. Metal-catalyzed couplings, preferably Suzuki reactions,can be performed according to standard methodology described above,preferably in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), an aqueous basesuch as aq Na₂CO₃, and a suitable solvent such as toluene, ethanol,dimethoxyethane (DME), or DMF.

The amino group in compound 1-10 can then be coupled with a heterocyclicacid P²—WCOOH (or a corresponding salt thereof P²—WCOOM², M² is Li, Naor K), according to standard procedures for amide bond formation (for areview, see: M. Bodansky and A. Bodansky, The Practice of PeptideSynthesis, Springer-Verlag, NY (1984)) or by reaction with acidchlorides WCOCl or activated esters WCO₂Rq (where Rq is a leaving groupsuch as pentafluorophenyl or N-succinimide) to form the product 1-11.The preferred reaction conditions for coupling with P²—WCOOH orP²—WCOOM² are: when W is a furan (optional protecting group P² notpresent), oxalyl chloride in dichloromethane (DCM) with DMF as acatalyst to form the acid chloride WCOCl and then coupling in thepresence of a trialkylamine such as N,N-diisopropylethylamine (DIEA);when W is a pyrrole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI) and 1-hydroxybenzotriazole-6-sulfonamidomethylhydrochloride (HOBt); and when W is an imidazole or triazole, thepreferred conditions are bromotripyrrolidinophosphoniumhexafluorophosphate (PyBrOP) and DIEA in a solvent such as DCM or DMF.

When W in compound 1-11 contains an optional protecting group P² asmentioned previously, it can be removed at this point. For example, whenW is imidazole optionally protected on nitrogen with2-(trimethylsilyl)ethoxymethyl (SEM), the SEM group can be removed witheither acidic reagents such as trifluoroacetic acid TFA or fluoridesources such as tertbutylammonium fluoride (TBAF) to obtain the desiredfinal product 1-12 (Y is CO, SO₂). The preferred reaction condition forthis deprotection is the treatment of the substrate with TBAF in thepresence or absence of ethylene diamine in a suitable solvent such asDMF to produce the final product 1-12.

An alternate synthetic route for the preparation of intermediates offormula 1-6 where Y is CO or SO₂ is shown in Scheme 2. The keyintermediate in this synthetic route is 4-substituted phenylglutaronitrile 2-2 which can be prepared from the corresponding 4-formylcompound 2-1 according to the literature procedures (EP 24776). It isunderstood that R^(x) in this synthetic route can be an appropriatelyprotected amine or a functional group which can be converted to an aminesuch as NO₂. R^(x) can be present in the starting material or it can beintroduced at an appropriate step as described in Scheme 1. The nitrilefunctions of phenylglutaronitrile 2-2 can be hydrolyzed to obtainphenylglutaramide 2-3 according to the appropriate literature procedures(For reference, see “Comprehensive Organic Transformations”, by RichardC. Larock, John Wiley & Sons. Inc, NY, (1999). In addition, diesterintermediate 2-6 (R^(y) is alkyl), which can be prepared usingprocedures analogous to literature procedures (Journal of the IndianChemical Society, 55(9), 897-901, (1978)), can also be converted tophenylglutaramide 2-3 according to the literature procedure (Synthesis,(11), 973-4, (1982)).

The phenylglutaramide 2-3 can be converted to desired cyclic urea 1-6 (Yis CO) by means of Hoffman rearrangement either via carbamateintermediate 2-5 with or without isolation (U.S. Pat. No. 6,022,968). Inaddition it is also understood that cyclic urea 1-6 (Y is CO) can bedirectly obtained from intermediate 2-3 when the Hoffman rearrangementis initiated with reagents such as Pb(OAc)₄ implementing minormodifications to literature procedures (WO 9943659). It is clear tothose who are skilled in the art, the R^(x) can be manipulated at theappropriate stage to install the amino function in intermediate 1-6 (Yis CO, SO₂). In addition, the carbamate 2-5 (R^(z) is t-Bu) can also beconverted to diamine 2-4 under acidic conditions, preferably TFA. Thediamine 2-4 can then be used as a precursor for the synthesis of cyclicureas and cyclic sulfonylureas 1-6 by the various methods described forthe formation of 1-6 in Scheme 1.

Scheme 3 illustrates another synthetic route for the preparation ofcyclic ureas, cyclic sulfonylureas where X is

and cyclic guanidines of Formula I where X is

For the illustration of synthetic strategy in this scheme, reagents andconditions are defined for the substrate where J is CH. As previouslymentioned in Scheme 1, it is understood that similar synthetic methodscan be utilized with minor modification when J is N.

Commercially available 2-phenyl-propane-1,2-diol 3-1 can be employed asthe starting material in this synthetic sequence which is protected togive 3-2. The examples of suitable O-protecting groups can be found in“Protective Groups in Organic Synthesis”, by Theodora W. Greene andPeter G. M. Wuts, John Wiley & Sons. Inc, NY, (1999). The preferredprotection of the diol is the conversion to the corresponding diacetate3-2 where P³ is Ac (Tetrahedron, 46(20), 7081, (1990)).

The conversion of intermediate 3-2 to amine 3-4 can be accomplished bytwo methods. In one method, halogenation, preferably bromination, of 3-2followed by either metal-catalyzed amination of the halo intermediate3-3 (where R^(x) is halogen) (for reviews, see: S. L. Buchwald, et al,Top. Curr. Chem., 219:131-209 (2001) and J. F. Hartwig in“Organopalladium Chemistry for Organic Synthesis,” Wiley Interscience,NY (2002)) can be employed. In the other method compound 3-2 can benitrated and the nitro intermediate 3-3 (where R^(x) is NO₂) (forreferences see; The Nitro Group in Organic Synthesis” by Noboru Ono,John Wiley & Sons. Inc,) is then reduced. The preferred method for thistransformation is nitration of the intermediate 3-2 with conc. HNO₃ toobtain compound 3-3 (R^(x) is NO₂), followed by the catalytichydrogenation to convert the nitro group to the corresponding aminogroup in 3-4.

The compounds of formula 3-6 can be obtained by ortho-halogenation,preferably bromination, of aniline substrate 3-4 to obtain intermediate3-5 (L³ is halogen), followed by metal-catalyzed coupling reaction ofthe latter with a suitable partner as previously described in Scheme 1to introduce R². The preferred conditions for bromination ofintermediate 3-4 are NBS in a suitable solvent such as DMF, DCM oracetonitrile. The metal-catalyzed couplings, preferably Suzukireactions, can be performed according to standard methodology asdescribed in Scheme 1, preferably in the presence of a palladium (0)catalyst such as tris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃) inthe presence of a nonaqueous base such as K₃PO₄ and a phosphine ligandsuch as 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos)in suitable solvents such as toluene, DME or dioxane.

The compounds in formula 3-7 can be prepared by reaction of compounds ofFormula 3-6 with carboxylic acids P²—WCOOH as previously described. Theprotecting group P³ in intermediate 3-7 can be then removed to unmaskthe diol function. The preferred method of deprotection involves thesaponification of diacetate 3-7 (P³ is Ac) with inorganic bases such asKOH in suitable solvents such as ethyl alcohol (EtOH). The diol functionof intermediate 3-8 can be transformed to diamine 3-10 as previouslydescribed in Scheme 1, via diazide 3-9, replacing catalytichydrogenation with an appropriate reduction method which does not reducean olefin, such as Zn/NH₄C1.

When X is a cyclic guanidine, the diamine can be reacted withappropriate guanidinylating reagents such S,S′-dimethylcyanodithioimidocarbonate,N-[bis(methylthio)methylene]methanesulfonamide and dimethylN-nitroimidodithiocarbonate (Australian Journal of Chemistry, 46(6),873, (1993), dimethyl N-nitroimidodithiocarbonate (WO 9204329) andmethyl [bis(methylthio)methylene]carbamate (U.S. Pat. No. 3,839,416) toafford compound 3-11 (Q is NR³).

When W in compound 3-11 contains an optional protecting group P² asmentioned previously it can be removed at this point as describedpreviously in Scheme 1, to obtain the final product 3-12.

When Q is a cyclic urea or sulfonylurea, the diamine 3-10 can also bereacted with carbonylating reagents and sulfonylating reagents asdescribed in Scheme 1 followed again by the removal of P² if present.

A synthetic route for the preparation of cyclic imides of Formula Iwhere X is

is shown in Scheme 4. It is clear to those who are skilled in the artthat, although the reagents and conditions are defined for the substratewhere J is CH in order to illustrate the synthetic methodology, similarsynthetic methods can be utilized with minor modification when J is N.

The 4-nitrophenylglutaric acid 4-4 can be employed as the keyintermediate in this synthetic route. This material can be prepared bydirect nitration of phenylglutaric acid 4-5. The preferred condition forthis transformation is the treatment of phenylglutaric acid 4-5 withconc. HNO₃ (WO 9923063). Alternatively, this substrate can be preparedstarting with 4-nitrobenzaldehyde 4-1 via intermediates 4-2 and 4-3utilizing preparative methods described in literature for the synthesisof phenylglutaric acid (Journal of Medicinal Chemistry, 47(8), 1900,(2004)). The construction of the imide ring structure can beaccomplished via either conversion of nitrophenyl glutaric acid 4-4 theto the corresponding anhydride 4-6 followed by ring opening with anamine R¹NH₂ and subsequent ring closure of the resulting amide acidintermediate to give 4-7. The 4-nitrophenylglutaric acid 4-4, can alsobe directly converted to imide 4-7 (R¹ is H) by fusing it with urea(Chemistry—A European Journal, 7(20), 4512, (2001)). In some cases R¹ isthe group desired in the final product. When the amine R¹NH₂ employed inthis reaction contains a protecting group such as p-methoxybenzyl (PMB),the unsubstituted imide 4-7, (R¹ is H) can be obtained by the removal ofthe p-methoxybenzyl group by known literature methods (For examples ofdeprotection methods see: Theodora W. Greene and Peter G. M. Wuts, JohnWiley and Sons, Inc., NY (1991)). The preferred method for thistransformation is to treat the intermediate 4-7 (R¹ is p-methoxybenzyl)with ammonium cerium (IV) nitrate (CAN) (Bull. Chem. Soc. Jpn. 58, 1413,(1985)).

The conversion of the nitro group of intermediate 4-7 to obtain aminocompound 4-8 can be accomplished by known literature methods asdescribed previously in Scheme 2. The preferred method for thistransformation is catalytic hydrogenation. The R² substituent, can beintroduced via ortho-halogenation of intermediate 4-8 andmetal-catalyzed coupling reactions of resulting product 4-9 (where L¹ ishalogen, preferably Br) as previously described to give 4-10.

Compound 4-11 can be prepared by reaction of compound 4-10 withcarboxylic acids P²—WCOOH as previously described in Scheme 1. When W incompound 4-11 contains optional protection P² as mentioned previously,it can be removed as described in Scheme 1 to obtain the final product4-12.

A synthetic route for the preparation of compounds of Formula I where Xis

is shown in Scheme 5. It is clear to those who are skilled in the artthat, although the reagents and conditions are defined for the substratewhere J is H in order to illustrate the synthetic methodology, similarsynthetic methods can be utilized with minor modification when J is N.

2-Phenyl-1-propene-1,3-disulfonic acid 5-1 (J. Amer. Chem. Soc., 66,1105-9, (1944)) can be employed as the starting material in thissynthesis (J is CH). This material can be subjected to catalytichydrogenation to obtain 5-2 which can then be nitrated as described inScheme 4 to obtain intermediate 5-3. Intermediate 5-3 can be convertedto anhydride 5-4 according to the literature procedure (Chem. Ber. 91,1512-15, (1958)). The cyclic sulfonimide 5-5 can be obtained fromintermediate 5-4 utilizing the synthetic methodology described in Scheme4 for the conversion of anhydride 4-6 to cyclic imide 4-7. In somecases, cyclization of an intermediate sulfonamidosulfonic acid may berequired using methods described in the literature (Ann., 657, 86-94(1962)), preferably using POCl₃. The nitro group of intermediate 5-5 canbe reduced to an amino group to obtain intermediate 5-6 which can becarried through the next 4 steps employing the chemistry described forthe conversion of intermediate 4-8 to 4-12 as described in Scheme 4.

Scheme 6 illustrates the synthetic route for the preparation of cycliccarbonates of Formula I where X is

and alternative routes for the preparation of cyclic ureas and cyclicsulfonylureas of Formula I where X is

(R¹ is H), respectively, and for cyclic guanidines of Formula I where Xis

(R¹ is H). Starting material 6-1 is a dihalonitro compound where leavinggroup L⁴ is chloro or preferably fluoro and where L⁵ is bromo or iodo.Compound 6-1 can be reacted with a dialkyl malonate, for example diethylmalonate (R^(x) is Et) or preferably dimethyl malonate (R^(x) is Me), ina polar aprotic solvent, such as N,N-dimethylacetamide (DMA),dimethylsulfoxide (DMSO) or preferably N,N-dimethylformamide (DMF), inthe presence of a base, such as KH, LiH, KOtBu or preferably NaH toafford compound 6-2.

The second halide L⁵ in compound 6-2 can then undergo a metal-catalyzedcoupling reaction with a boronic acid or a boronate ester (Suzukireactions where R²M¹ is R²B(OH)₂, for example, cyclohexan-1-enyl boronicacid, or R²B(OR)₂ where (OR)₂ is pinacolato, respectively) or with tinreagents (Stille reactions, where R²M¹ is R²Sn(alkyl)₃) in the presenceof a suitable palladium catalyst such as Pd(Ph₃P)₄ or preferablydichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)(Pd(dppf)Cl₂) and an appropriate base, such as Cs₂CO₃ or preferablyK₃PO₄ to give compound 6-3. For reviews of these couplings reactions,see N. Miyaura, A. Suzuki, Chem. Rev., 95, 2457 (1995), J. K. Stille,Angew. Chem., Int. Ed. Engl., 25, 508-24 (1986) and A. Suzuki inMetal-Catalyzed Coupling Reactions, F. Deiderich, P. Stang, Eds.,Wiley-VCH, Weinheim (1988).

The nitro group in compound 6-3 can be reduced to an amino group by areducing agent which will not reduce an olefin, such as iron powder inthe presence of NH₄Cl in a solvent such as aqueous ethanol, to formamine 6-4.

The amino group in compound 6-4 can then be coupled with a heterocyclicacid P²—WCOOH (or a corresponding salt thereof P²—WCOOM², M² is Li, Naor K), according to the procedures for amide bond formation as describedin Scheme 1 to form the amide product 6-5 (P² is optional protectinggroup as defined in Scheme 1). The optional protecting group on W, ifpresent, in compound 6-5, such as 2-(trimethylsilyl)ethoxymethyl (SEM)optionally used to protect a nitrogen when W contains an imidazole ortriazole, can be removed under the conditions described in Scheme 1,preferably acidic conditions and most preferably with trifluoroaceticacid, to give compound 6-6. Alternatively the optional protecting groupP² can be removed with a fluoride reagent, preferably tetrabutylammoniumfluoride in a suitable solvent such as DMF or THF.

The two ester groups in compound 6-6 can be selectively reduced by anappropriate reducing agent, such as sodium borohydride in the presenceof suitable solvents, such as a mixture of methanol and tert-butanol, toform compound 6-7.

Diol 6-7 can be reacted with an appropriate carbonylation agent, such asphosgene, carbonyldiimidazole, bis(4-nitrophenyl)carbonate or preferablytriphosgene, in the presence of a base, such as pyridine or lutidine, inan organic solvent, such as THF, to give compound 6-8.

Diol 6-7 can also serve as a precursor to diamine 6-9 by the methodologydescribed in Scheme 3 for the conversion of diol 3-8 to diamine 3-10.Diamine 6-9 is useful for the synthesis of cyclic ureas 6-10 (R¹ is H)and cyclic sulfonylureas 6-11 (R¹ is H) as described for the synthesisof compound 1-6 in Scheme 1, and, for the synthesis of cyclic guanidines6-12 (R¹ is H) as described for the synthesis of compound 3-10 in Scheme3).

An alternative route to intermediate 6-4 of Scheme 6 is illustrated inScheme 7 and is particularly useful for the synthesis of the compounds6-8, 6-10, 6-11 and 6-12 as shown in Scheme 6 where J is N.

Compound 7-1 may serve as a starting material where L¹ is chloro orpreferably fluoro and can be substituted by a malonate ester asdescribed in Scheme 6 to give compound 7-2. Reduction of nitro compound7-2 to amine 7-3 can be carried out by any of a number of standardreduction methods (as reviewed in M. Hudlicky, “Reductions in OrganicChemistry,” Wiley, NY (1984)), preferably with hydrogen over a suitablecatalyst such as palladium on carbon in an appropriate solvent such asethanol.

Halogenation, preferably bromination, of amine 7-3 to introduce L² canbe carried as described in Scheme 1 for the preparation of compound 1-9.Suzuki coupling with a boronic acid or boronic ester R²M¹ as describedin Scheme 6 can then provide intermediate 6-4 which is carried on to thefinal compounds as also described in Scheme 6.

Scheme 8 illustrates a route to the preparation of2-imidazolecarboxylates of Formula 8-5 where R^(a) is H or C₍₁₋₄₎alkyl,and R^(d) is H, alkyl, —CN, or —CONH₂ that are used as intermediates inthe synthesis of compounds of Formula I where W is imidazole.

Imidazoles of Formula 8-1 where R^(a) is H or C₍₁₋₄₎alkyl, and R^(c) isH, C₍₁₋₄₎alkyl or —CN are either commercially available or, in the casewhere R^(c) is —CN, are readily available from commercially availablealdehydes (8-1 where R^(c) is CHO) by reaction with hydroxylaminesfollowed by dehydration with a suitable reagent such as phosphorusoxychloride or acetic anhydride (Synthesis, 677, 2003). Imidazoles ofFormula 8-1 are protected with a suitable group (P¹) such as amethoxymethylamine (MOM), or preferably a SEM group to give compounds ofFormula 8-2 (see Theodora W. Greene and Peter G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, Inc., NY (1991)).

Imidazoles of Formula 8-2, where R^(c) is —CN, are halogenated with asuitable reagent such as N-bromosuccinimide or N-iodosuccinimide undereither electrophilic conditions in a solvent such as DCM or CH₃CN orunder radical conditions in the presence of an initiator such asazobis(isobutyronitrile) (AIBN) in a solvent such as CCl₄ to givecompounds of Formula 8-3 where L⁸ is a leaving group (preferably bromoor iodo). Halogen-magnesium exchange on compounds of Formula 8-3provides the organomagnesium species, which is then reacted with asuitable electrophile to provide compounds of Formula 8-4. The preferredconditions for halogen-magnesium exchange are using an alkyl-magnesiumreagent, preferably isopropylmagnesium chloride in a suitable solventsuch as THF at temperatures between −78° C.-to 0° C. The preferredelectrophiles are ethyl chloroformate or ethyl cyanoformate. Forexamples of halogen-magnesium exchange on cyanoimidazoles see J. Org.Chem. 65, 4618, (2000).

For imidazoles of Formula 8-2, where R^(c) is not —CN, these may beconverted directly to imidazoles of Formula 8-4 by deprotonation with asuitable base such as an alkyllithium followed by reaction with anelectrophile as described above for the organomagnesium species. Thepreferred conditions are treating the imidazole with n-butyllithium inTHF at −78° C. and quenching the resulting organolithium species withethyl chloroformate (for examples, see Tetrahedron Lett., 29, 3411-3414,(1988)).

The esters of Formula 8-4 may then be hydrolyzed to carboxylic acids (Mis H) or carboxylate salts (M is Li, Na, or K,) of Formula 8-5 using oneequivalent of an aqueous metal hydroxide (MOH) solution, preferablypotassium hydroxide in a suitable solvent such as ethanol or methanol.Synthesis of compounds of Formula 8-5 where R^(d) is —CONH₂ isaccomplished by first treating compounds of Formula 8-4 where R^(c) is—CN with an appropriate alkoxide such as potassium ethoxide to convertthe cyano group to an imidate group (Pinner reaction) followed byhydrolysis of both the ester and imidate groups with two equivalents ofan aqueous metal hydroxide solution.

Scheme 9 illustrates a route to 2-imidazolecarboxylates of Formula 9-3or 9-5 where R^(e) is chloro or bromo, and M is H, Li, K, or Na that areused as intermediates in the synthesis of compounds of Formula I where Wis imidazole.

Compounds of Formula 9-1 are first prepared by protection ofcommercially available ethyl imidazolecarboxylate according to themethods outlined in Scheme 8, preferably with a SEM group.

Compounds of Formula 9-2 are prepared by reaction of compounds ofFormula 9-1 with one equivalent of an appropriate halogenating reagent,such as NBS or N-chlorosuccinimide (NCS) in a suitable solvent such asCH₃CN, DCM or DMF at 25° C. Compounds of Formula 9-4 are prepared byreaction of compounds of Formula 9-1 with two equivalents of anappropriate halogenating reagent, such as NBS or NCS in a suitablesolvent such as CH₃CN or DMF at temperatures between 30° C. to 80° C.Imidazoles of Formula 9-3 and 9-5 are then obtained from the respectiveesters by hydrolysis as described in Scheme 8.

Scheme 10 illustrates a method for the preparation of imidazoles ofFormula 10-3 where R^(f) is —SCH₃, —SOCH₃, or —SO₂CH₃, M is H, Li, K, orNa that are used as intermediates in the synthesis of compounds ofFormula I where W is imidazole. Imidazole 10-1 (WO 1996011932) isprotected according to the methods described in Scheme 8, preferablywith a SEM protecting group to give compounds of Formula 10-2. Esterhydrolysis according to the procedure in Scheme 8 gives compounds ofFormula 10-3 where R^(f) is —SCH₃. Oxidation of 2-methylthioimidazolesof Formula 10-2 with one equivalent of an appropriate oxidant, followedby ester hydrolysis according to the procedure in Scheme 8 givescompounds of Formula 10-3 where R^(f) is —SOCH₃. Oxidation with twoequivalents of an appropriate oxidant, followed by ester hydrolysisaccording to the procedure in Scheme 8 gives compounds of Formula 10-3where R^(f) is —SO₂CH₃. The preferred reagent for oxidation is MCPBA inDCM. When compounds of Formula I contain a sulfide, either acyclic orcyclic, the sulfide can be further oxidized to the correspondingsulfoxides or sulfones. Sulfoxides can be obtained by oxidation using anappropriate oxidant such as one equivalent of meta-chloroperbenzoic acid(MCPBA) or by treatment with NaIO₄ (see, for example, J. Med. Chem., 46:4676-86 (2003)) and sulfones can be obtained using two equivalents ofMCPBA or by treatment with 4-methylmorpholine N-oxide and catalyticosmium tetroxide (see, for example, PCT application WO 01/47919). Also,both sulfoxides and sulfones can be prepared by using one equivalent andtwo equivalents of H₂O₂ respectively, in the presence of titanium (IV)isopropoxide (see, for example, J. Chem. Soc., Perkin Trans. 2,1039-1051 (2002)).

EXAMPLES

The following examples are for exemplary purposes only and are in no waymeant to limit the invention.

Example 1 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A flask charged with imidazole-4-carbonitrile (0.50 g, 5.2 mmol)(Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl)(0.95 mL, 5.3 mmol), K₂CO₃ (1.40 g, 10.4 mmol), and acetone (5 mL) wasstirred for 10 h at RT. The mixture was diluted with ethyl acetate(EtOAc) (20 mL) and washed with water (20 mL) and brine (20 mL) and theorganic layer dried over MgSO₄. The crude product was eluted from a 20-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.80 g (70%) of thetitle compound as a colorless oil: Mass spectrum (CI (CH₄), m/z) Calcd.for C₁₀H₁₇N₃OSi, 224.1 (M+H). found 224.1.

b)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g,3.1 mmol) (as prepared in the previous step) in CCl₄ (10 mL) was addedN-bromosuccinimide (NBS) (0.61 g, 3.4 mmol) and azobis(isobutyronitrile)(AIBN, catalytic), and the mixture was heated at 60° C. for 4 h. Thereaction was diluted with EtOAc (30 mL), washed with NaHCO₃ (2×30 mL),brine (30 mL), the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.73 g (77%) of a yellow solid:Mass spectrum (CI (CH₄), m/z) Calcd. for C₁₀H₁₆BrN₃OSi, 302.0/304.0(M+H). found 302.1/304.1.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile(0.55 g, 1.8 mmol) (as prepared in the previous step) in tetrahydrofuran(THF) (6 mL) at −40° C. was added drop wise a solution of 2 Misopropylmagnesium chloride (1-PrMgCl) in THF (1 mL). The reaction wasallowed to stir for 10 min at −40° C. and then cooled to −78° C., andethyl cyanoformate (0.30 g, 3.0 mmol) was added. The reaction allowed toattain RT and stirred for 1 h. The reaction was quenched with satd aqNH₄Cl, diluted with EtOAc (20 mL), washed with brine (2×20 mL). Theorganic layer was dried over Na₂SO₄ and then concentrated. The titlecompound was eluted from a 20-g SPE cartridge (silica) with 30%EtOAc/hexane to give 0.40 g (74%) of a colorless oil: Mass spectrum(ESI, m/z): Calcd. for C₁₃H₂₁N₃O₃Si, 296.1 (M+H). found 296.1.

d)4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (0.40 g, 1.3 mmol) (as prepared in the previous step)in ethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and thereaction was stirred for 10 min and then concentrated to give 0.40 g(100%) of the title compound as a yellow solid: ¹H-NMR (CD₃OD; 400 MHz):δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H).Mass spectrum (ESI-neg, m/z): Calcd. for C₁₁H₁₆KN₃O₃Si, 266.1 (M-K).found 266.0.

e) 2-(4-Nitro-benzylidine)-malonic acid diethyl ester

A solution of 3.00 g (19.9 mmol) of 4-nitro-benzaldehyde in toluene (30mL) was treated with 3.62 mL (23.8 mmol) of malonic acid diethyl esterand 0.5 mL of piperidine. The mixture was heated to 100° C. for 24 h,cooled to room temperature (RT), diluted with toluene (80 mL) and washedwith water (1×100 mL), saturated aqueous NaHCO₃ (1×100 mL), and 1.0 Maqueous HCl (1×100 mL). The organic layer was dried (MgSO₄) andconcentrated in vacuo. Silica gel chromatography of the residue with 25%EtOAc-hexane afforded 5.09 g (87%) of the title compound: ¹H-NMR (CDCl₃;400 MHz): δ 8.25 (d, 2H, J=8.8 Hz), 7.77 (s 1H), 7.63 (d, 2H, J=8.8 Hz),4.35 (qd, 4H, J=7.2, 2.0 Hz), 1.30 (t, 6H, J=7.2 Hz).

f) 2,4-Bis-ethoxycarbonyl-3-(4-nitro-phenyl)-pentanedioic acid diethylester

A solution of 1.42 g (20.8 mmol) of solid NaOEt in EtOH (30 mL) wastreated with 3.43 mL (22.6 mmol) of malonic acid diethyl ester at RT for20 min. This mixture was treated with a solution of 5.09 g (17.4 mmol)of 2-(4-nitro-benzylidine)-malonic acid diethyl ester (as prepared inthe previous step) at RT for 6 h. AcOH (5 mL) was added, and the mixturestirred for 5 min. The mixture was partitioned between water (50 mL) andCH₂Cl₂ (125 mL). The organic layer was separated, dried (MgSO₄), andconcentrated in vacuo to afford 7.32 g (93%) of the title compound:¹H-NMR (CDCl₃; 400 MHz): δ 8.12 (d, 2H, J=8.8 Hz), 7.58 (d, 2H, J=8.8Hz), 5.30 (s, 1H), 4.34-4.28 (m, 1H), 4.26-4.11 (m, 9H), 1.32-1.20 (m,12H).

g) 3-(4-Nitro-phenyl)-pentanedioic acid

A suspension of 7.32 g (16.1 mmol) of2,4-bis-ethoxycarbonyl-3-(4-nitro-phenyl)-pentanedioic acid diethylester (as prepared in the previous step) in concentrated HCl (15 mL) washeated to 100° C. for 22 h. The mixture was cooled to RT, and theresulting precipitate was filtered, washed with cold water, andair-dried to afford 3.58 g (88%) of the title compound as an off-whitesolid: ¹H-NMR (CD₃OD; 400 MHz): δ 8.12 (d, 2H, J=8.8 Hz), 7.58 (d, 2H,J=8.8 Hz), 3.77-3.68 (m, 1H), 2.87-2.66 (m, 4H).

h) 4-(4-Nitro-phenyl)-piperidine-2,6-dione

A mixture of 250 mg (0.987 mmol) of 3-(4-nitro-phenyl)-pentanedioic acid(as prepared in the previous step) and 119 mg (1.98 mmol) of urea washeated to 150° C. for 40 min (until all solid melted and gas evolutionstopped). The mixture was cooled to RT, taken up in EtOAc (70 mL),washed with saturated aqueous NaHCO₃ (2×40 mL), dried (MgSO₄), andconcentrated in vacuo to afford 52.0 mg (22%) of the title compound as abrown solid: ¹H-NMR (CDCl₃; 400 MHz): δ 8.28 (d, 2H, J=8.8 Hz), 7.44 (d,2H, J=8.8 Hz), 3.64-3.54 (m, 1H), 3.04-2.96 (m, 2H), 2.86-2.76 (m, 2H).

Alternatively, the title compound can be obtained in the followingmanner: A solution of 500 mg (1.97 mmol) of3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step)in 50 mL dioxane was cooled to 10° C. and treated with 229 μL (2.96mmol) of methyl chloroformate and 936 μL (6.71 mmol) of triethylaminefor 7.2 h. A solution of 0.5 M ammonia in dioxane (15.8 mL, 7.90 mmol)was added at 10° C. and the mixture stirred at RT for 72 h. The mixturewas filtered through Celite, the filter cake washed with EtOAc, and thesolvents were evaporated in vacuo. The residue was treated with solid1.30 g (15.8 mmol) of NaOAc and acetic anhydride (4 mL) and heated to100° C. for 1 h. The mixture was cooled to RT and concentrated to halfthe original volume. The residue was taken up in EtOAc (100 mL), washedwith saturated aqueous NaHCO₃ (1×75 mL), brine (1×75 mL), and water(1×75 mL). The organic layer was dried (MgSO₄) and concentrated invacuo. Silica gel chromatography of the residue on a 50-g VarianMegaBond Elut SPE column with 50-60% EtOAc-hexane afforded 197 mg (43%)of the title compound as an off-white solid (see spectrum above).

i) 4-(4-Amino-phenyl)-piperidine-2,6-dione

A solution of 197 mg (0.841 mmol) of4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previousstep) in methyl alcohol (MeOH) (15 mL) was hydrogenated over 10% Pd/C at20 psi for 5 h at RT. The mixture was filtered through Celite, thefilter cake was washed with MeOH, and the solvents were evaporated invacuo to afford 106 mg (62%) of the title compound as an off-whitesolid: Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₂N₂O₂, 205.1 (M+H).found 205.1.

j) 4-(4-Amino-3-bromo-phenyl)-piperidine-2,6-dione

A solution of 106 mg (0.519 mmol) of4-(4-amino-phenyl)-piperidine-2,6-dione (as prepared in the previousstep) in CH₂Cl₂ (20 mL) was cooled to 0° C. and treated with 92.4 mg(0.519 mmol) of NBS for 35 min. The mixture was diluted with CH₂Cl₂ (50mL) and washed with saturated aqueous NaHCO₃ (2×40 mL) and water (1×40mL). The organic layer was dried (MgSO₄) and concentrated in vacuo toafford 138 mg (94%) of the title compound as a tan solid: Mass spectrum(ESI, m/z): Calcd. for C₁₁H₁₁N₂O₂Br, 283.0/285.0 (M+H). found283.1/285.1.

k) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-piperidine-2,6-dione

A solution of 69.0 mg (0.244 mmol) of4-(4-amino-3-bromo-phenyl)-piperidine-2,6-dione (as prepared in theprevious step) in toluene (10 mL) and dioxane (10 mL) was treated with30.7 mg (0.244 mmol) of cyclohex-1-enylboronic acid, 104 mg (0.487 mmol)of K₃PO₄, and 34.2 mg (0.0975 mmol) of2-(dicyclohexylphosphino)biphenyl. The mixture was degassed viasonication, placed under Ar, treated with 5.50 mg (0.0244 mmol) ofPd(OAc)₂, and heated to 90° C. for 5 h. The mixture was diluted withEtOAc (30 mL) and washed with water (2×20 mL). The organic layer wasdried (MgSO₄) and concentrated in vacuo to afford 73.5 mg (106%, somesolvent trapped) of the title compound as a tan solid: Mass spectrum(ESI, m/z): Calcd. for C₁₇H₂₀N₂O₂, 285.2 (M+H). found 285.2.

l) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

A solution of 73.5 mg (0.259 mmol) of4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-2,6-dione (as preparedin the previous step) in CH₂Cl₂ (20 mL) was treated with 64.4 mg (0.388mmol) of PyBroP, 86.8 mg (0.284 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in this Example, step (d)), and 135 μL(0.775 mmol) of DIEA at RT for 2 h. The mixture was diluted with CH₂Cl₂(50 mL) and washed with saturated aqueous NaHCO₃ (2×30 mL). The organiclayer was dried (MgSO₄) and concentrated in vacuo to afford 70.0 mg(51%) of the title compound as an off-white solid: Mass spectrum (ESI,m/z): Calcd. for C₂₈H₃₅N₅O₄Si, 534.3 (M+H). found 534.2.

m) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

A solution of 70.0 mg (0.131 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide (asprepared in the previous step) in CH₂Cl₂ (10 mL) was treated with EtOH(2 drops) and TFA (3 mL) at RT for 1.5 h. Solvents were removed invacuo. Purification of the residue by reverse phase high pressure liquidchromatography (RP-HPLC) (C18) with 10-80% CH₃CN in 0.1% TFA/H₂O over 30min afforded 5.3 mg (8%) of the title compound as a white solid: ¹H-NMR(CD₃OD; 400 MHz): δ 8.18 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.24 (dd, 1H,J=8.4, 2.4 Hz), 7.15 (d, 1H, J=2.4 Hz), 5.85-5.78 (m, 1H), 3.48-3.38 (m,1H), 2.90-2.71 (m, 4H), 2.32-2.22 (m, 4H), 1.90-1.73 (m, 4H). Massspectrum (ESI, m/z): Calcd. for C₂₂H₂₁N₅O₃, 404.2 (M+H). found 404.0.

Example 2 Another Method for the Preparation of4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide fromExample 1

a) 3-(4-Nitro-phenyl)-pentanedioic acid

A flask charged with concentrated H₂SO₄ (400 mL) was cooled to 0° C. andtreated with 50.0 g (240 mmol) of 3-phenyl-pentanedioic acid portionwiseover 20 min and with fuming HNO₃ (10 mL) dropwise over 20 min. Themixture was stirred at RT for 3 h, poured over ice (amount equivalent to1000 mL), and the precipitate was filtered, washed with cold water,air-dried, and dried in a vacuum dessicator. The solid was trituratedwith a minimum amount of CH₃CN, filtered, and air-dried. The filtratewas concentrated and triturated again with a minimum amount of CH₃CN,filtered, and air-dried to afford a second batch. The two batches werecombined to afford 56.9 g (94%) of the title compound as an off-whitesolid: ¹H-NMR (DMSO-d₆; 400 MHz): δ 8.15 (d, 2H, J=8.8 Hz), 7.58 (d, 2H,J=8.8 Hz), 3.62-3.50 (m, 1H), 2.79-2.57 (m, 4H).

b) 4-(4-Nitro-phenyl)-dihydro-pyran-2,6-dione

A flask was charged with 20.0 g (79.0 mmol) of3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step)and 22.4 mL (237 mmol) of acetic anhydride. The mixture was heated to80° C. for 1 h, cooled to RT, and treated slowly with ether until theproduct began to precipitate. After allowing the solid to fullyprecipitate, the solid was filtered, washed with ether, and air-dried toafford 13.0 g (70%) of the title compound as an off-white solid: ¹H-NMR(CDCl₃; 400 MHz): δ 8.28 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz),3.64-3.53 (m, 1H), 3.22-3.13 (m, 2H), 2.96-2.85 (m, 2H).

c) 1-(4-Methoxy-benzyl)-4-(4-nitro-phenyl)-piperidine-2,6-dione

A solution of 12.6 g (53.6 mmol) of4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in the previousstep) in THF (160 mL) was treated with 9.04 mL (6.96 mmol) of4-methoxy-benzylamine at RT for 2 h. Solvents were evaporated in vacuo.The residue was dissolved in 1.0 N HCl (200 mL) and extracted with EtOAc(2×250 mL). The combined organic layers were washed with water (1×200mL), dried (MgSO₄) and concentrated in vacuo. The residue was treatedwith acetic anhydride (200 mL) and triethylamine (30 mL), and heated to85° C. for 1.5 h. The mixture was concentrated in vacuo, treated with1.0 N HCl (200 mL), and extracted with EtOAc (3×200 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ (1×200 mL) andwater (1×200 mL), dried (MgSO₄), and concentrated in vacuo. The solidwas triturated with hexane using sonication, filtered and air-dried toafford 16.5 g (87%) of the title compound as light tan solid: Massspectrum (ESI, m/z): Calcd. for C₁₉H₂₁N₂O, 325.1 (M−OCH₃+2H). found325.0.

d) 4-(4-Nitro-phenyl)-piperidine-2,6-dione

A suspension of 22.8 g (64.2 mmol) of1-(4-methoxy-benzyl)-4-(4-nitro-phenyl)-piperidine-2,6-dione (asprepared in the previous step) in CH₃CN (150 mL) was treated with 70.4 g(128 mmol) of ceric ammonium nitrate (CAN) as a solution in water (100mL). The mixture was stirred at RT for 5 h, diluted with water (100 mL),and extracted with EtOAc (2×150 mL). The combined organic layers werewashed with saturated aqueous NaHCO₃ (1×100 mL) and water (1×100 mL).The combined aqueous layers were extracted with EtOAc (1×100 mL). Thecombined organic layers were dried (MgSO₄) and concentrated in vacuo.The solid residue was triturated with a minimum amount of CH₃CN,filtered, and air-dried. The filtrate was concentrated and trituratedagain with a minimum amount of CH₃CN, filtered, and air-dried as asecond batch. The two batches were combined to afford 7.00 g (47%) as anoff-white solid: ¹H-NMR (CDCl₃; 400 MHz): δ 8.26 (d, 2H, J=8.8 Hz), 7.97(br s, 1H), 7.42 (d, 2H, J=8.8 Hz), 3.62-3.52 (m, 1H), 3.02-2.93 (m,2H), 2.84-2.74 (m, 2H).

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

The title compound was prepared from4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previousstep) using the same procedures found in Example 1, steps (i)-(m).Spectra are identical to the spectra of Example 1, step (m).

Example 3 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

a)4-[4-Amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-2,6-dione

A solution of 600 mg (2.12 mmol) of4-(4-amino-3-bromo-phenyl)-piperidine-2,6-dione (as prepared in Example1, step (j)) in toluene (20 mL) and dioxane (20 mL) was treated with 900mg (4.24 mmol) of K₃PO₄, 424 mg (2.76 mmol) of4,4-dimethyl-cyclohex-1-enylboronic acid, and 297 mg (0.848 mmol) of2-(dicyclohexylphosphino)biphenyl. The mixture was degassed viasonication, placed under Ar, treated with 47.6 mg (0.212 mmol) ofPd(OAc)₂, and heated to 80° C. for 2.5 h. The mixture was diluted withEtOAc (100 mL) and washed with water (2×70 mL). The aqueous layer wasextracted with EtOAc (100 mL), the combined organic layers were dried(MgSO₄) and concentrated in vacuo. Silica gel chromatography of theresidue on a 50-g Varian MegaBond Elut SPE column with 25-50%EtOAc-hexane afforded 140 mg (21%) of the title compound as a tan solid:Mass spectrum (ESI, m/z): Calcd. for C₁₉H₂₄N₂O₂, 313.2 (M+H). found313.1.

b) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

A solution of 140 mg (0.448 mmol) of4-[4-amino-3-(4,4-dimethyl-cyclhex-1-enyl)-phenyl]-piperidine-2,6-dione(as prepared in the previous step) in CH₂Cl₂ (10 mL) was treated with313 mg (0.672 mmol) of PyBroP, 151 mg (0.493 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 1, step (d)), and 234 μL (1.34mmol) of DIEA at RT for 30 min. The mixture was diluted with CH₂Cl₂ (30mL) and washed with saturated aqueous NaHCO₃ (1×30 mL). The organiclayer was dried (MgSO₄) and concentrated in vacuo. Silica gelchromatography of the residue with 10-42% EtOAc-hexane afforded 192 mg(76%) of the title compound as an off-white solid: Mass spectrum (ESI,m/z): Calcd. for C₃₀H₃₉N₅O₄Si, 562.3 (M+H). found 562.0.

c) 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide

A solution of 190 mg (0.338 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide(as prepared in the previous step) in CH₂Cl₂ (10 mL) was treated withMeOH (200 μL) and TFA (3 mL) at RT for 1.5 h. MeOH (30 mL) was added,the mixture was concentrated to half volume, MeOH (15 mL) was added, andthe solvents were removed completely in vacuo at <35° C. Silica gelchromatography of the residue with 25-75% EtOAc-hexane afforded 92.9 mg(64%) of the title compound as a white solid: ¹H-NMR (CD₃OD; 400 MHz): δ8.22 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.26 (dd, 1H, J=8.4, 2.4 Hz), 7.18(d, 1H, J=2.4 Hz), 5.79-5.75 (m, 1H), 3.52-3.42 (m, 1H), 2.93-2.76 (m,4H), 2.37-2.30 (m, 2H), 2.12-2.07 (m, 2H), 1.62 (t, 2H, J=5.6 Hz), 1.10(s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₂₄H₂₅N₅O₃, 432.2 (M+H).found 432.1.

Example 4 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amidetrifluoroacetic acid salt

a) [4-(2-Hydroxy-1-hydroxymethyl-ethyl)-phenyl]-carbamic acid tert-butylester

A mixture of 2-(4-amino-phenyl)-propane-1,3-diol (1.6 g, 9.6 mmol, J.Med. Chem., 40(25), 4030-4052, (1997)), di-tert-butyl dicarbonate(BOC)₂O (2.30 g, 10.5 mmol), THF (200 mL), water (100 mL) and Na₂CO₃(1.12 g, 10.5 mmol) was stirred at RT overnight. The reaction mixturewas diluted with EtOAc (200 mL) and satd brine (200 mL). The organiclayer was separated and the aq layer was extracted with EtOAc (2×100mL). The organic layers were combined, dried (Na₂SO₄) and concentrated.The residue obtained was purified on silica (20-100% EtOAc-hexane) toobtain the title compound (1.2 g, 47%): Mass spectrum (ESI, m/z): Calcd.for C₁₄H₂₁NO₄, 290.3 (M+Na). found 290.0.

b) [4-(2-Amino-1-aminomethyl-ethyl)-phenyl]-carbamic acid tert-butylester

To a suspension of [4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-carbamicacid tert-butyl ester (267 mg, 1.00 mmol, as prepared in the previousstep) in DCM (10 mL) and Et₃N (0.35 mL, 2.5 mmol), methanesulfonylchloride (MsCl) (0.15 mL, 2.0 mmol) was added dropwise at 0° C. Theresulting mixture was stirred at RT for 30 min, diluted with DCM (10 mL)and washed with satd NaHCO₃ (20 mL). The organic layer was separated,dried (Na₂SO₄) and concentrated to afford methanesulfonic acid2-(4-tert-butoxycarbonylamino-phenyl)-3-methanesulfonyloxy-propyl ester,which was dried in vacuo and directly used in next step: Mass spectrum,(ESI, m/z): Calcd. for C₁₆H₂₅NO₈S₂, 446.1 (M+Na). found 446.0.

To a solution of crude methanesulfonic acid2-(4-tert-butoxycarbonylamino-phenyl)-3-methanesulfonyloxy-propyl ester(as prepared above) in DMF (10 mL) was added NaN₃ (130 mg, 2.00 mmol).The resulting mixture was heated at 70° C. overnight. The reactionmixture was allowed to cool to RT, diluted with ether (10 mL) and washedwith water (3×10 mL). The organic layer was separated, dried (Na₂SO₄)and concentrated. The residue obtained was purified on silica (10%EtOAc-hexane) to afford[4-(2-azido-1-azidomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester(206 mg, 65% overall): ¹H-NMR (CD₃OD; 400 MHz): δ 7.33 (d, 2H, J=8.6Hz), 7.07 (d, 2H, J=8.6 Hz), 3.48 (m, 4H), 2.93 (m, 1H), 1.42 (s, 9H).

[4-(2-Azido-1-azidomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester(240 mg, 0.757 mmol, as prepared above) was hydrogenated at 40 psi H₂over 10% Pd/C (120 mg) for 1 h. The reaction mixture was filteredthrough a pad of Celite, concentrated and dried in vacuo to afford[4-(2-amino-1-aminomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester(169 mg, 64%): ¹H-NMR (CD₃OD; 400 MHz): δ 7.35 (d, 2H, J=8.6 Hz), 7.12(d, 2H, J=8.6 Hz), 2.90 (m, 2H), 2.79 (m, 2H), 2.69 (m, 1H), 1.42 (s,9H).

c) [4-(2-Oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butylester

A solution of [4-(2-amino-1-aminomethyl-ethyl)-phenyl]-carbamic acidtert-butyl ester (as prepared in the previous step, 739 mg, 2.78 mmol)and bis 4-nitrophenylcarbonate (850 mg, 2.79 mmol) in 1,2-dichloroethane(250 mL) was heated at reflux for 24 h. The reaction mixture wasconcentrated in vacuo and the resulting residue was purified on silica(50% EtOAc-hexane-5% MeOH-EtOAc) to afford the title compound (437 mg,53%): Mass spectrum (ESI, m/z): Calcd. for C₁₅H₂₁N₃O₃, 292.3 (M+H).found 292.0.

d) [2-Bromo-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acidtert-butyl ester

To a solution of [4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamicacid tert-butyl ester (as prepared in the previous step, 29 mg, 0.10mmol) in CH₃CN (1 mL), NBS (19.5 mg, 0.100 mmol) was added. Theresulting mixture was stirred overnight and concentrated to half thevolume. The resulting precipitate was collected by filtration to obtainthe title compound (12 mg, 32%): Mass spectrum (ESI, m/z): Calcd. forC₁₅H₂₀BrN₃O₃, 370.0 and 372.0 (M+H). found 370.1 and 372.1.

e) 5-(4-Amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyrimidin-2-one

[2-Bromo-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acidtert-butyl ester (99 mg, 0.26 mmol, as prepared in the previous step)was dissolved in TFA (1 mL). The resulting mixture was stirred at RT for30 min and concentrated in vacuo. The residue obtained was dried invacuo for 1 h and dissolved in EtOH (0.5 mL) and toluene (1 mL). To thissolution cyclohex-1-enyl boronic acid (20.5 mg, 0.16 mmol), 2M Na₂CO₃(0.5 mL, 1 mmol) and Pd (PPh₃)₄ (30 mg, 0.025 mmol) were added. Theresulting mixture was heated at 80° C. overnight. The reaction mixturewas allowed to cool to RT and extracted with EtOAc (2×10 mL). The EtOAclayers were combined, dried (Na₂SO₄) and concentrated in vacuo. Theresidue obtained was purified on silica (2% MeOH-EtOAc) to afford thetitle compound (31 mg) contaminated with Ph₃PO, which was used in thenext step without further purification: Mass spectrum (ESI, m/z): Calcd.for C₁₆H₂₁N₃O, 272.1 (M+H). found 272.1.

f) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

5-(4-Amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyrimidin-2-one (22 mg,as prepared in the previous step) was coupled to4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 1, step (d), 27.2 mg,0.0890 mmol) as described in Example 1, step (1) to obtain the titlecompound (14 mg, over two steps) after purification on silica (3%MeOH-EtOAc): Mass spectrum (ESI, m/z): Calcd. for C₂₇H₃₆N₆O₃Si, 521.2(M+H). found 521.1.

g) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amidetrifluoroacetic acid salt

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide(as prepared in the previous step, 14 mg, 0.026 mmol) was dissolved inDCM (1 mL), EtOH (30 μL) and TFA (0.3 mL). The resulting mixture wasstirred overnight and concentrated. The residue obtained was subjectedto RP-HPLC eluting with 20% to 100% CH₃CN in 0.1% TFA/H₂O over 20 min ona C18 column to obtain the title compound (1.1 mg, 8%): ¹H-NMR(CD₃OD/CDCl₃; 400 MHz): δ 8.23 (d, 1H, J=8.0 Hz), 7.90 (s, 1H), 7.20(dd, 1H, J=8.0, 2.2 Hz), 7.09 (d, 1H, J=2.2 Hz), 5.75 (br s, 1H), 3.47(4H, m), 3.17 (m, 1H), 2.22-2.33 (m, 4H), 1.72-1.83 (m, 4H). Massspectrum (ESI, m/z): Calcd. for C₂₁H₂₂N₆O₂, 391.3 (M+H). found 391.2.

Example 5 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide

a) [4-(1,1-Dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acidtert-butyl ester

[4-(2-Amino-1-aminomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester(as prepared in Example 4, step (b), 30.4 mg, 0.114 mmol) and sulfamide(15.4 mg, 0.802 mmol) in pyridine (0.7 mL) was heated at reflux for 4 h.The reaction mixture was concentrated in vacuo, and the residue waspurified on silica (20%-70% EtOAc-hexane) to obtain the title compound(24 mg, 64%): ¹H-NMR (DMSO-d₆; 400 MHz): δ 9.35 (br s, 1H), 7.45 (m,2H), 7.15 (m, 2H), 6.73 (m, 2H), 3.52 (m, 2H), 3.27 (m, 2H), 2.85 (m,1H), 1.52 (s, 9H).

b) 2-Bromo-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenylamine

[4-(1,1-Dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acidtert-butyl ester (as prepared in the previous step, 100 mg, 0.305 mmol)was dissolved in TFA (1 mL). The resulting solution was stirred at RTfor 30 min and concentrated in vacuo. The residue obtained (74.3 mg) wasdried in vacuo for 1 h and dissolved in HOAc (2 mL). The resultingmixture was cooled to 0° C. and NBS (42.6 mg, 0.239 mmol) was added. Theresulting mixture was stirred for 30 min, washed with aq NaHCO₃ (2 mL)and concentrated. The residue was purified on silica (20-100%EtOAc-hexane) to obtain the title compound (49 mg, 52%): ¹H-NMR (CD₃OD;400 MHz): δ 7.23 (d, 1H, J=2.0 Hz), 6.93 (dd, 1H, J=8.2, 2.0 Hz), 6.78(d, 1H, J=8.2 Hz), 3.63 (m, 2H), 3.32 (m, 2H), 2.82 (m, 1H).

c)2-Cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenylamine

2-Bromo-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenylamine (asprepared in the previous step, 46.9 mg, 0.153 mmol) was reacted withcyclohexane-1-enyl boronic acid (24.1 mg, 0.191 mmol) according to theSuzuki coupling procedure of Example 4, step (e) and purified on silica(20-100% EtOAc-hexane) to afford the title compound (30.7 mg, 65%): Massspectrum (ESI, m/z): Calcd. for C₁₅H₂₁N₃O₂S, 308.1 (M+H). found 308.1.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide

2-Cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenylamine(as prepared in the previous step, 30.7 mg, 0.100 mmol) was coupled to4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 1, step (d), 33.6 mg, 0.260mmol) as described in Example 1, step (1) to obtain the title compound(14 mg, 25%) after purification on silica (20-50% EtOAc-hexane): Massspectrum (ESI, m/z): Calcd. for C₂₆H₃₆N₆O₄SSi, 557.2 (M+H). found 556.8.

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide(as prepared in the previous step, 17.8 mg, 0.0320 mmol) in DMF (35 μL)and ethylenediamine (13 μL, 0.18 mmol), solid tetrabutylammoniumfluoride (TBAF) (25 mg, 0.090 mmol) was added. The resulting solutionwas stirred at 60° C. for 12 h. The reaction mixture was concentrated invacuo and the resulting residue purified on silica (20-100%EtOAc-hexane) to afford the title compound (9.3 mg, 68%): ¹H-NMR (CD₃OD;400 MHz): δ 8.19 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 7.18 (dd, 1H, J=8.7,2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.81 (br s, 1H), 3.62 (m, 2H), 3.35 (m,2H), 2.93 (m, 1H), 2.24-2.34 (m, 4H), 1.82-1.90 (m, 4H). Mass spectrum(ESI, m/z): Calcd. for C₂₀H₂₂N₆O₃S, 427.1 (M+H). found 427.2.

Example 6 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-5-hydroxymethyl-phenyl]-amide

TFA (0.3 mL) was added to a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide(as prepared in Example 5, step (d), 21 mg, 0.030 mmol) in DCM (1 mL)and EtOH (30 μL). The resulting mixture was stirred at RT for 2 h andconcentrated in vacuo. The residue obtained was purified on silica(20-50% EtOAc-hexane) to obtain the title compound (8.0 mg, 46%): ¹H-NMR(CD₃OD; 400 MHz): δ 8.10 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 5.78 (brs, 1H), 4.7 (ABq, 1H, J=16 Hz), 4.48 (ABq, 1H, J=16 Hz), 4.3 (m, 1H),3.87 (m, 1H), 3.52 (m, 1H), 3.6 (m, 1H), 3.18 (m, 1H), 2.62 (br s, 1H),2.22-2.34 (m, 4H), 1.72-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₁H₂₄N₆O₄S, 439.1 (M−H₂O+H). found 439.2.

Example 7 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amidetrifluoroacetic acid salt

a) [4-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamicacid tert-butyl ester

A mixture of [4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acidtert-butyl ester (as prepared in Example 4, step (c), 376 mg, 1.29mmol), powdered K₂CO₃ (744 mg, 5.39 mmol), Bu₄NBr (41.9 mg, 0.130 mmol),1,2-dichloroethane (8 mL), and Me₂SO₄ (0.5 mL) was heated to 60° C. insealed tube overnight. The reaction mixture was allowed to cool to RT,and the inorganic solids were filtered off. The filter cake was washedwith 1:1 dioxane/DCM (3×20 mL). The organic layers were combined andconcentrated in vacuo. The residue obtained was purified on silica(20-100% EtOAc-hexane) to afford the title compound (259 mg, 63%): Massspectrum (ESI, m/z): Calcd. for C₁₇H₂₅N₃O₃, 320.2 (M+H). found 320.0.

b) 5-(4-Amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-onetrifluoroacetic acid salt

[4-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acidtert-butyl ester (as prepared in the previous step, 106 mg, 0.333 mmol)was dissolved in TFA (2 mL). The resulting mixture was stirred at RT for30 min and concentrated. The residue obtained was dried in vacuo for 30min and redissolved in DCM (5 mL). The resulting solution was cooled to0° C. and NBS (64 mg, 0.35 mmol) was added. The reaction mixture wasstirred at RT for 30 min and treated with DCM (20 mL) and satd aq NaHCO₃(20 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated to afford the title compound (92 mg, 92%), which wasdirectly used in next step without further purification. Mass spectrum(ESI, m/z): Calcd. for C₁₂H₁₆BrN₃O, 298.0 and 300.0 (M+H). found 298.2and 300.2.

c)5-(4-Amino-3-cyclohex-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one

5-(4-Amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-onetrifluoroacetic acid salt (as prepared in the previous step, 92 mg, 0.30mmol) was reacted with cyclohex-1-enyl boronic acid (48.7 mg, 0.375mmol) according to the Suzuki coupling procedure of Example 4, step (e)and purified on silica (2% MeOH-EtOAc) to afford the title compound (35mg, 38%): Mass spectrum (ESI, m/z): Calcd. for C₁₈H₂₅N₃O, 300.2 (M+H).found 300.3.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide(as prepared in the previous step, 41 mg, 0.13 mmol) was coupled to4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 1, step (d), 50 mg, 0.16mmol) as described in Example 1, step (1) to obtain the title compound(66 mg, 87%) after purification on silica (50-100% EtOAc-hexane): Massspectrum (ESI, m/z): Calcd. for C₂₉H₄₀N₆O₃Si, 549.2 (M+H). found 549.2.

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amidetrifluoroacetic acid salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide(as prepared in the previous step, 66 mg, 0.12 mmol) in DMF (2 mL),solid TBAF (109 mg, 0.410 mmol) was added. The resulting mixture wasstirred at 60° C. for 6 h. The DMF was removed in vacuo, and theresulting residue was purified on RP-HPLC eluting with 20% to 100% CH₃CNin 0.1% TFA/H₂O over 20 min on a C18 column to obtain the title compound(26 mg, 52%): ¹H-NMR (CDCl₃; 400 MHz): δ 9.50 (s, 1H), 8.45 (d, 1H,J=8.4 Hz), 7.75 (s, 1H), 7.24 (dd, 1H, J=8.4, 2.0 Hz), 7.08 (d, 1H,J=2.0 Hz), 5.87 (br s, 1H), 3.62 (m, 2H), 3.35 (m, 3H), 2.94 (s, 6H),2.22-2.34 (m, 4H), 1.72-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₃H₂₆N₆O₂, 419.2 (M+H). found 419.3.

Example 8 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

a)5-[4-Amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,3-dimethyl-tetrahydro-pyrimidin-2-one

The title compound was prepared according to the Suzuki couplingprocedure of Example 4, step (e), using 4,4-dimethyl-cyclohex-1-enylboronic acid in place of cyclohex-1-enylboronic acid: Mass spectrum(ESI, m/z): Calcd. for C₂₈H₂₉N₃O, 328.2 (M+H). found 328.3.

b) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

The title compound was synthesized from5-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,3-dimethyl-tetrahydro-pyrimidin-2-one(as prepared in the previous step) as described in Example 1, step (1):Mass spectrum (ESI, m/z): Calcd. for C₃₁H₄₄N₆O₃Si, 577.3 (M+H). found577.2.

c) 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amidetrifluoroacetic acid salt

The title compound was synthesized from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide(as prepared in the previous step) as described in Example 7, step (e).¹H-NMR (CDCl₃; 400 MHz): δ 9.55 (s, 1H), 8.43 (d, 1H, J=8.4 Hz), 7.73(s, 1H), 7.24 (dd, 1H, J=8.4, 2.1 Hz), 7.06 (s, 1H), 5.82 (br s, 1H),3.60 (m, 2H), 3.33 (m, 3H), 3.13 (s, 6H), 2.28-2.35 (m, 2H), 2.08-2.17(m, 2H), 1.62 (m, 2H), 1.16 (s, 6H); Mass spectrum (ESI, m/z): Calcd.for C₂₅H₃₀N₆O₂, 447.2 (M+H). found 447.3.

Example 9 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohept-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

a)5-(4-Amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one

A solution of5-(4-amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-onetrifluoroacetic acid salt (as prepared in Example 7, step (b), 105 mg,0.352 mmol), cycloheptene-1-yl boronic acid (74 mg, 0.52 mmol), K₃PO₄(224 mg, 1.05 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃) (32 mg, 0.034 mmol), and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (57.5 mg, 0.350mmol) in toluene (0.7 mL) was heated at 100° C. under Ar for 1 h. Thereaction mixture was allowed to cool to RT and filtered. The filter cakewas washed with DCM (2×10 mL). The organic layers were combined, dried(Na₂SO₄) and concentrated in vacuo. The residue obtained was purified onsilica (20-100% EtOAc-hexane) to afford the title compound (95 mg, 86%):Mass spectrum (ESI, m/z): Calcd. for C₁₉H₂₇N₃O, 314.2 (M+H). found314.3.

b) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohept-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

5-(4-Amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one(as prepared in the previous step, 47.5 mg, 0.151 mmol) was coupled to4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 1, step (d), 27.2 mg,0.0890 mmol) as described in Example 1, step (1) to obtain the titlecompound (82 mg, 96%) after purification on silica (20-100%EtOAc-hexane): Mass spectrum (ESI, m/z): Calcd. for C₃₀H₄₂N₆O₃Si, 563.3(M+H). found 563.1.

c) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohept-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amidetrifluoroacetic acid salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohept-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide(as prepared in the previous step, 86 mg, 0.15 mmol) in DMF (2 mL),solid TBAF (213 mg, 0.816 mmol) was added. The resulting mixture wasstirred at 60° C. for 6 h. The DMF was removed in vacuo, and theresulting residue was purified on RP-HPLC eluting with 20-100% CH₃CN in0.1% TFA/H₂O over 20 min on a C18 column to obtain the title compound(39 mg, 47%): ¹H-NMR (CD₃OD; 400 MHz): δ 8.15 (d, 1H, J=8.4 Hz), 8.02(s, 1H), 7.22 (dd, 1H, J=8.4, 2.1 Hz), 7.13 (d, 1H, J=2.1 Hz), 5.98 (t,1H, J=6.4 Hz), 3.53-3.38 (m, 5H), 2.96 (m, 6H), 2.54 (m, 2H), 2.42 (m,2H), 1.92 (m, 2H), 1.65-1.83 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₄H₂₈N₆O₂, 433.2 (M+H). found 433.2.

Example 10 4-Cyano-1H-pyrrole-2-carboxylic acid[2-cyclohept-1-enyl-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide

A mixture of5-(4-amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one(as prepared in Example 9, step (a), 21 mg, 0.067 mmol),4-cyanopyrrolecarboxylic acid (Canadian J. Chem. 59: 2673 (1981)). (24.6mg, 0.180 mmol), EDCI (19.4 mg, 0.101 mmol), HOBt (9.2 mg, 0.068 mmol),DIEA (35 μL, 0.20 mmol) in DCM (0.5 mL) was stirred at RT overnight. Thereaction mixture was concentrated in vacuo and the residue was purifiedRP-HPLC eluting with 20% to 100% CH₃CN in 0.1% TFA/H₂O over 20 min on aC18 column to obtain the title compound (4.2 mg, 14%): ¹H-NMR (CD₃OD;400 MHz): δ 7.58 (d, 1H, J=1.5 Hz), 7.44 (d, 1H, J=8.2 Hz), 7.15-7.24(m, 3H), 5.93 (t, 1H, J=6.5 Hz), 3.38-3.61 (m, 5H), 2.96 (m, 6H), 2.48(m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.45-1.23 (m, 4H); Mass spectrum(ESI, m/z): Calcd. for C₂₅H₂₉N₅O₂, 432.2 (M+H). found 432.2.

Example 11 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide

a)[4-(2,6-Dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester

A mixture of[4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acidtert-butyl ester (as prepared in Example 5, step (a), 327 mg, 1.00mmol), powdered K₂CO₃ (1.88 g, 10.0 mmol) and MeI (0.64 mL, 15 mmol) inDMF (10 mL) was heated at 50° C. for 12 h in a sealed tube. The reactionmixture was allowed to cool to RT, and the inorganic solids werefiltered off. The filter cake was washed with 1:1 dioxane/DCM (3×20 mL).The organic layers were combined and concentrated in vacuo. The residueobtained was purified on silica (20-100% EtOAc-hexane) to afford thetitle compound (233 mg, 65.6%): Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₅N₃O₄S, 356.1 (M+H). found 356.1.

b)[2-Bromo-4-(2,6-dimethyl-1,1-dioxo-1λ^(6-[)1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester

The title compound was prepared from[4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester (as prepared in the previous step) according tothe procedure described in Example 5, step (b): Mass spectrum (ESI,m/z): Calcd. for C₁₁H₁₆BrN₃O₂S, 334.0 and 336.0 (M+H). found 334.0 and336.0.

c)2-Cyclohex-1-enyl-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenylamine

The title compound was prepared from[2-bromo-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester (as prepared in the previous step) according tothe procedure described in Example 4, step (e): Mass spectrum (ESI,m/z): Calcd. for C₁₇H₂₅N₃O₂S, 336.1 (M+H). found 336.2.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide

The title compound was prepared from2-cyclohex-1-enyl-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenylamine(as prepared in the previous step) according to the procedure describedin Example 1, step (1): Mass spectrum (ESI, m/z): Calcd. forC₂₈H₄₀N₆O₄SSi, 585.2 (M+H). found 584.9.

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amidetrifluoroacetic acid salt

The title compound was prepared from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide(as prepared in the previous step) according to the SEM deprotectionprocedure described in Example 9, step (b): ¹H-NMR (CDCl₃; 400 MHz): δ11.85 (br s, 1H), 9.54 (s, 1H,), 8.37 (d, 1H, J=8.4 Hz), 7.73 (d, 1H,J=2.1 Hz), 7.38 (dd, 1H, J=8.4, 2.1 Hz), 7.04 (s, 1H), 5.98 (m, 1H),3.85 (m, 2H), 3.46 (m, 2H), 3.33 (m, 2H), 2.35-2.20 (m, 4H), 1.65-1.92(m, 4H): Mass spectrum (ESI, m/z): Calcd. for C₂₂H₂₆N₆O₂S, 455.1 (M+H).found 455.2.

Example 12 4-Cyano-1H-imidazole-2-carboxylic acid[4-(2-cyanoimino-hexahydro-pyrimidin-5-yl)-2-cyclohex-1-enyl-phenyl]-amide

a) Acetic acid 3-acetoxy-2-(4-amino-3-cyclohex-1-enyl-phenyl)-propylester

To a solution of acetic acid 3-acetoxy-2-(4-amino-phenyl)-propyl ester(Tetrahedron, 46(20), 7081, (1990), 1.2 g, 5.0 mmol) in DCM (50 mL), NBS(903 mg, 5.07 mol) was added at 0° C. The resulting mixture was stirredat RT for 2 h and subjected to the usual work up to obtain acetic acid3-acetoxy-2-(4-amino-3-bromo-phenyl)-propyl ester (1.4 g, 89%) which wasdirectly used in the next step.

The title compound was prepared according to the Suzuki couplingprocedure of Example 9, step (a) using acetic acid3-acetoxy-2-(4-amino-3-bromo-phenyl)-propyl ester (as prepared above)and cyclohex-1-enyl boronic acid: Mass spectrum, (ESI, m/z): Calcd. forC₁₉H₂₅NO₄, 332.1 (M+H). found 332.1.

b) Acetic acid3-acetoxy-2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-propylester

Acetic acid 3-acetoxy-2-(4-amino-3-cyclohex-1-enyl-phenyl)-propyl ester(as prepared in the previous step) was coupled to4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 1, step (d)) as describedin Example 1, step (1) to obtain the title compound: Mass spectrum (ESI,m/z): Calcd. for C₃₀H₄₀N₄O₆Si, 581.2 (M+H). found 581.0.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide

To a solution of acetic acid3-acetoxy-2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-propylester (as prepared in the previous step, 580 mg, 1.00 mmol) in i-PrOH(15 mL), 2N NaOH (1 mL, 2 mmol) was added. The reaction mixture wasstirred at RT for 1 h, and DCM (200 mL) and water (200 mL) were added.The organic layer was separated, dried (Na₂SO₄) and concentrated. Theresidue was purified on silica (40% EtOAc-hexane) to obtain the titlecompound (312 mg, 63%): Mass spectrum (ESI, m/z): Calcd. forC₂₆H₃₆N₄O₄Si, 497.2 (M+H). found 497.0.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (asprepared in the previous step) was converted to the correspondingdiazide,4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(2-azido-1-azidomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide,as previously described in Example 4, step (b), which was directly usedin the next step without further purification.

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(2-azido-1-azidomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide(as prepared above, 546 mg, 1.00 mmol) was dissolved in THF (1 mL),water (2 mL) and MeOH (10 mL). To this solution NH₄Cl (534 mg, 25.0mmol) and Zn powder (653 mg, 10.0 mmol) were added with cooling. Theresulting mixture was stirred at RT for 30 min and filtered through athin pad of Celite. The filter cake was washed with MeOH (2×10 mL). Thefiltrate was concentrated, dissolved in 5% i-PrOH/DCM and washed withsatd aq NaHCO₃ (20 mL). The organic layer was dried (Na₂SO₄) andconcentrated to obtain the title compound (207 mg, 42%): Mass spectrum(ESI, m/z): Calcd. for C₂₆H₃₈N₆O₂Si, 495.3 (M+H). found 495.2.

e) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[4-(2-cyanoimino-hexahydro-pyrimidin-5-yl)-2-cyclohex-1-enyl-phenyl]-amide

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide(as prepared in the previous step, 15 mg, 0.030 mmol) in DCM (10 mL),dimethyl N-cyanodithioiminocarbonate (4.2 mg, 0.28 mmol) was added. Theresulting solution was heated at reflux for 4 h. The reaction mixturewas allowed to cool to RT and was concentrated in vacuo. The residueobtained was purified on silica (20-100% EtOAc-hexane) to obtain thetitle compound (11 mg, 62%): Mass spectrum (ESI, m/z): Calcd. forC₂₈H₃₆N₈O₂Si, 545.3 (M+H). found 545.1.

f) 4-Cyano-1H-imidazole-2-carboxylic acid[4-(2-cyanoimino-hexahydro-pyrimidin-5-yl)-2-cyclohex-1-enyl-phenyl]-amide

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[4-(2-cyanoimino-hexahydro-pyrimidin-5-yl)-2-cyclohex-1-enyl-phenyl]-amide(as prepared in the previous step) was subjected to SEM deprotection asdescribed in Example 9, step (c) to obtain the title compound: ¹H-NMR(CD₃OD/CDCl₃; 400 MHz): δ 8.25 (d, 1H, J=8.4 Hz), 7.73 (s, 1H), 7.24(dd, 1H, J=8.4, 2.1 Hz), 7.08 (d, 1H, J=2.1 Hz), 5.85 (br s, 1H),3.4-3.6 (m, 4H), 3.1-3.2 (m, 1H), 2.22-2.34 (m, 4H), 1.77-1.90 (m, 4H):Mass spectrum, (ESI, m/z): Calcd. for C₂₂H₂₇N₈O₂, 415.2 (M+H). found415.2.

Example 13 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4(2methanesulfonylimino-hexahydro-pyrimidin-5-yl)-phenyl]-amide

a) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(2-methanesulfonylimino-hexahydro-pyrimidin-5-yl)-phenyl]-amide

A solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide(as prepared in Example 12, step (d), 250 mg, 0.506 mmol) andN-(bis-methylsulfanyl-methylene)-methanesulfonamide (Australian Journalof Chemistry, 46(6), 873, (1993), 100 mg, 0.506 mmol) in1,2-dichloroethane (20 mL) was heated at reflux for 4 h. The reactionmixture was concentrated, and the residue was purified on silica(20-100% EtOAc-hexane) to obtain the title compound (117 mg, 39%): Massspectrum, (ESI, m/z): Calcd. for C₂₈H₃₉N₇O₄SSi, 598.2 (M+H). found598.2.

b) 4-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl4(2-methanesulfonylimino-hexahydro-pyrimidin-5-yl)-phenyl]-amide

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(2-methanesulfonylimino-hexahydro-pyrimidin-5-yl)-phenyl]-amide(as prepared in the previous step) was subjected to SEM deprotection asdescribed in Example 9, step (c) to obtain the title compound: ¹H-NMR(DMSO-d₆; 400 MHz): δ 14.2 (br s, 1H), 9.69 (s, 1H), 8.25 (s, 1H), 7.82(d, 1H, J=8.4 Hz), 7.44 (s, 1H), 7.17 (dd, 1H, J=8.4, 2.2 Hz), 7.08 (d,1H, J=2.2 Hz), 5.65 (br s, 1H), 3.32-3.36 (m, 4H), 2.98-3.05 (m, 1H),2.68 (s, 3H), 2.02-2.18 (m, 4H), 1.45-1.68 (m, 4H): Mass spectrum (ESI,m/z): Calcd. for C₂₂H₂₅N₇O₃S, 468.2 (M+H). found 468.3.

Example 14 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]-amide

a) 1-Methyl-4-(4-nitro-phenyl)-piperidine-2,6-dione

A solution of 399 mg (1.70 mmol) of4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in Example 2,step (b)) in THF (8 mL) was treated with 1.10 mL (2.21 mmol) of 2.0 Mmethylamine in THF. The mixture was stirred at RT for 45 min,concentrated in vacuo, taken up in 1 N aqueous HCl (10 mL), andextracted with EtOAc (2×20 mL). The combined organic layers were dried(MgSO₄) and concentrated in vacuo. The residue was taken up in aceticanhydride (7 mL), treated with triethylamine (1 mL) and heated to 80° C.for 1 h. The solvents were removed in vacuo. The residue was taken up inEtOAc (20 mL) and washed successively with 1 N aqueous HCl, saturatedaqueous NaHCO₃, and water (1×10 mL each). The organic layer was dried(MgSO₄) and concentrated in vacuo. Silica gel chromatography of theresidue with 25-50% EtOAc-hexane afforded 348 mg (83%) of the titlecompound as an off-white solid: ¹H-NMR (CDCl₃; 400 MHz): δ 8.25 (d, 2H,J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.56-3.45 (m, 1H), 3.21 (s, 3H),3.10-3.01 (m, 2H), 2.88-2.77 (m, 2H).

b) 4-(4-Amino-phenyl)-1-methyl-piperidine-2,6-dione

A suspension of 348 mg (1.40 mmol) of1-methyl-4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in theprevious step) in MeOH (10 mL) was hydrogenated over 10% Pd/C at 20 psifor 1 h at RT. The mixture was filtered through Celite, the filter cakewas washed with MeOH, and the solvents were evaporated in vacuo toafford 289 mg (94%) of the title compound as an off-white solid: Massspectrum (ESI, m/z): Calcd. for C₁₂H₁₄N₂O₂, 219.1 (M+H). found 219.1.

c) 4-(4-Amino-3-bromo-phenyl)-1-methyl-piperidine-2,6-dione

A solution of 289 mg (1.32 mmol) of4-(4-amino-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in theprevious step) in CH₂Cl₂ (15 mL) was treated portionwise with 224 mg(1.29 mmol) of solid NBS for 20 min. The mixture was diluted with CH₂Cl₂(30 mL) and washed with saturated aqueous NaHCO₃ (2×30 mL). The organiclayer was dried (MgSO₄) and concentrated in vacuo. Silica gelchromatography of the residue with 25-50% EtOAc-hexane afforded 265 mg(67%) of the title compound as a tan solid: Mass spectrum (ESI, m/z):Calcd. for C₁₂H₁₃N₂O₂Br, 297.0/299.0 (M+H). found 297.0/299.0.

d) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-1-methyl-piperidine-2,6-dione

A suspension of 265 mg (0.892 mmol) of4-(4-amino-3-bromo-phenyl)-1-methyl-piperidine-2,6-dione (as prepared inthe previous step) in toluene (15 mL) and dioxane (15 mL) was treatedwith 379 mg (1.78 mmol) of K₃PO₄, 146 mg (1.16 mmol) ofcyclohex-1-enylboronic acid, and 125 mg (0.357 mmol) of2-(dicyclohexylphosphino)-biphenyl. The mixture was degassed viasonication, placed under Ar, treated with 20.0 mg (0.00892 mmol) ofPd(OAc)₂, and heated to 80° C. for 2.5 h. The mixture was diluted withEtOAc (70 mL) and washed with water (2×50 mL). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo. Silica gelchromatography of the residue on a 50-g Varian MegaBond Elut SPE columnwith 25-50% EtOAc-hexane afforded 266 mg (100%) of the title compound asa tan solid: Mass spectrum (ESI, m/z): Calcd. for C₁₈H₂₂N₂O₂, 299.2(M+H). found 299.1.

e) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]-amide

A solution of 266 mg (0.891 mmol) of4-(4-amino-3-cyclohex-1-enyl-phenyl)-1-methyl-piperidine-2,6-dione (asprepared in the previous step) in CH₂Cl₂ (10 mL) was treated with 623 mg(1.34 mmol) of PyBroP, 300 mg (0.981 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 1, step (d)), and 466 μL (2.67mmol) of DIEA at RT for 16 h. The mixture was diluted with CH₂Cl₂ (30mL) and washed with saturated aqueous NaHCO₃ (1×30 mL). The organiclayer was dried (MgSO₄) and concentrated in vacuo. Silica gelchromagography of the residue on a 50-g Varian MegaBond Elut SPE columnwith 25% EtOAc-hexane afforded 130 mg (27%) of the title compound as anoff-white solid: Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₇N₅O₄Si,548.3 (M+H). found 547.9.

f) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]-amide

A solution of 130 mg (0.237 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]-amide(as prepared in the previous step) in CH₂Cl₂ (10 mL) was treated withMeOH (200 μL) and TFA (3 mL) at RT for 1.25 h. MeOH (30 mL) was added,the mixture was concentrated to half volume, MeOH (20 mL) was added, andthe solvents were removed completely in vacuo at <35° C. Silica gelchromatography of the residue on a 50-g Varian MegaBond Elut SPE columnwith 25-50% EtOAc-hexane and by RP-HPLC (C18) with 10-80% CH₃CN in 0.1%TFA/H₂O over 30 min afforded 8.0 mg (8%) of the title compound as awhite solid: ¹H-NMR (CD₃OD; 400 MHz): δ 8.19 (d, 1H, J=8.4 Hz), 8.03 (s,1H), 7.24 (dd, 1H, J=8.4, 2.4 Hz), 7.16 (d, 1H, J=2.4 Hz), 5.87-5.82 (m,1H), 3.47-3.37 (m, 1H), 3.16 (s, 3H), 2.96-2.91 (m, 4H), 2.33-2.25 (m,4H), 1.92-1.77 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₃N₅O₃,418.2 (M+H). found 418.1.

Example 15 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2-oxo-[1,3]dioxan-5-yl)-phenyl]-amide

a) 2-(3-Bromo-4-nitro-phenyl)-malonic acid dimethyl ester

To a suspension of NaH (364 mg, 9.08 mmol) in 10 mL of DMF at 0° C. wasadded malonic acid dimethyl ester (519 μL, 4.54 mmol). The resultingmixture was warmed to RT and stirred for 0.5 h under Ar.2-Bromo-4-fluoro-1-nitro-benzene (500 mg, 2.27 mmol) was added to themixture and the reaction was stirred at RT for 16 h under Ar. Themixture was then treated with 2 mL of satd aq NH₄Cl followed by 10 mL ofH₂O and extracted with DCM (3×10 mL). The combined extracts were washedwith water (10 mL), brine (5 mL) and dried (Na₂SO₄). Removal of thesolvent in vacuo followed by flash chromatography of the residue onsilica gel (1:4 hexane-DCM) gave 604 mg (80%) of a yellow-green oilcontaining the pure title compound as a mixture of di-ester (A) and itsenol tautomer (B): ¹H-NMR (CD₃OD; 400 MHz): A: δ 8.48 (d, 1H, J=2.5 Hz),8.21 (dd, 1H, J=8.8, 2.5 Hz), 7.85 (d, 1H, J=8.8 Hz), 5.34 (s, 1H), 3.81(s, 6H). B: δ 7.85 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=1.9 Hz), 7.54 (dd,1H, J=8.4, 1.9 Hz), 4.68 (s, 1H), 3.80 (s, 6H).

b) 2-(3-Cyclohex-1-enyl-4-nitro-phenyl)-malonic acid dimethyl ester

To a mixture of 2-(3-bromo-4-nitro-phenyl)-malonic acid dimethyl ester(as prepared in the previous step, 300 mg, 0.903 mmol),cyclohexane-1-enyl boronic acid (125 mg, 0.994 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (Pd(dppf)Cl₂—CH₂Cl₂) (66.0 mg, 0.0903 mmol) in 5mL of DMF was added K₃PO₄ (765 mg, 3.61 mmol). The resulting mixture wasstirred at 60° C. for 9 h under Ar. After cooling to RT, the mixture wastreated with 50 mL of EtOAc, washed with H₂O (3×10 mL) and brine (10mL). The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel with 10%EtOAc-hexane to afford 210 mg (70%) of the title compound as a yellowoil: Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₉NO₆, 334.1 (M+H). found334.0.

c) 2-(4-Amino-3-cyclohex-1-enyl-phenyl)-malonic acid dimethyl ester

A mixture of 2-(3-cyclohex-1-enyl-4-nitro-phenyl)-malonic acid dimethylester (as prepared in the previous step, 200 mg, 0.600 mmol), ironpowder (168 mg, 3.00 mmol) and NH₄Cl (321 mg, 6.00 mmol) in 6 mL ofethanol was stirred at 80° C. for 16 h. After cooling to RT, the mixturewas treated with 30 mL of H₂O and extracted with EtOAc (3×20 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by flash chromatography on silica gel (30%EtOAc-hexane) to give 129 mg (71%) of the title compound as a faintyellow oil: Mass spectrum (ESI, m/z): Calcd. for C₁₇H₂₁NO₄, 304.2 (M+H).found 304.1.

d)2-(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-malonicacid dimethyl ester

To a mixture of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-malonic aciddimethyl ester (as prepared in the previous step, 100 mg, 0.330 mmol),potassium4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate(as prepared in Example 1, step (d), 106 mg, 0.346 mmol) andbromotripyrrolidinophosphonium hexafluoro-phosphate (PyBroP) (154 mg,0.330 mmol) in 3 mL of DMF was added N,N-diisopropylethylamine (DIEA)(0.172 mL, 0.990 mmol). After stirring at RT for 16 h, the mixture wastreated with 50 mL of EtOAc and washed with H₂O (2×15 mL), brine (15 mL)and dried (Na₂SO₄). The organic solvent was evaporated and the residuewas purified by flash chromatography on silica gel (5-10% EtOAc-hexane)to give 118 mg (85%) of the title compound as a colorless oil: Massspectrum (ESI, m/z): Calcd. for C₂₈H₃₆N₄O₆Si, 553.2 (M+H). found 552.6.

e)2-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-malonicacid dimethyl ester

To a solution of2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-malonicacid dimethyl ester (as prepared in the previous step, 145 mg, 0.262mmol) in 1.0 mL of DCM (CH₂Cl₂) was added 1.0 mL of TFA. After stirringat RT for 4 h, the mixture was concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (20-30% EtOAc-hexane) togive 93 mg (84%) of the title compound as a white solid: Mass spectrum(ESI, m/z): Calcd. for C₂₂H₂₂N₄O₅, 423.1 (M+H). found 422.8.

f) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide

To a mixture of2-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-malonicacid dimethyl ester (as prepared in the previous step, 30.0 mg, 0.0710mmol) and NaBH₄ (13.4 mg, 0.355 mmol) in 1 mL of tert-butyl alcohol(t-BuOH) at 80° C. was added MeOH (50 μL) over 5 min. The resultingmixture was stirred at 80° C. for 16 h under Ar. After cooling to RT,the mixture was treated with 10% aq citric acid to a pH of 7. Themixture was then treated with 30 mL of EtOAc, washed with H₂O (5 mL) andbrine (10 mL). The organic layer was dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography on silica gelwith 1-5% MeOH-DCM to afford 14.1 mg (61%) of the title compound as awhite solid: ¹H-NMR (CD₃OD; 400 MHz): δ 8.00 (s, 1H), 7.54 (dd, 1H,J=8.2, 2.3 Hz), 7.46 (d, 1H, J=2.3 Hz), 7.27 (d, 1H, J=8.2 Hz), 5.59 (m,1H), 3.71-3.84 (m, 4H), 3.29 (m, 1H), 2.15-2.29 (m, 4H), 1.67-1.84 (m,4H). Mass spectrum (ESI, m/z): Calcd. for C₂₀H₂₂N₄O₃, 367.2 (M+H). found366.8.

g) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2-oxo-[1,3]dioxan-5-yl)-phenyl]-amide

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (asprepared in the previous step, 5.4 mg, 0.015 mmol) and pyridine (3.0 μL,0.037 mmol) in 0.5 mL of THF at −78° C. was added a solution oftriphosgene (1.8 mg, 0.0061 mmol) in 0.5 mL of DCM. The resultingmixture was warmed to RT and continued to stir for 1 h under Ar. Removalof the solvent under reduced pressure followed by flash chromatographyof the residue on silica gel (1-2% MeOH-DCM) gave 2.8 mg (48%) of thetitle compound as a white solid: ¹H-NMR (CD₃OD; 400 MHz): δ 8.01 (s,1H), 7.66 (dd, 1H, J=8.6, 2.3 Hz), 7.59 (d, 1H, J=2.3 Hz), 7.29 (d, 1H,J=8.6 Hz), 5.66 (m, 1H), 4.65 (dd, 2H, J=10.9, 10.9 Hz), 4.45 (dd, 2H,J=10.9, 4.9 Hz), 3.72 (m, 1H), 2.24 (m, 4H), 1.70-1.88 (m, 4H). Massspectrum (ESI, m/z): Calcd. for C₂₁H₂₀N₄O₄, 393.2 (M+H). found 393.1.

The following examples are produced according to procedures of previousexamples with the corresponding reagents as indicated in the tablebelow:

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 164-Cyano-1H-imidazole-2- carboxylic acid {4-[1,3-bis-(2-hydroxy-ethyl)-2-oxo- hexahydro-pyrimidin-5- yl]-2-cyclohex-1-enyl-phenyl}-amide

Ex. 4, steps (a)-(c); Ex 7 Br(CH₂)₂OSi— t-BuMe₂ (Aldrich Chemical Co.)17 4-Cyano-1H-imidazole-2- carboxylic acid [4-(1,3-diethyl-2-oxo-hexahydro- pyrimidin-5-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)- phenyl]-amide

Ex. 4, steps (a)-(c); Ex 7 EtI;  

  (Combi-Blocks, Inc.) 18 4-Cyano-1H-imidazole-2- carboxylic acid[2-(4,4- diethyl-cyclohex-1-enyl)- 4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5- yl)-phenyl]-amide

Ex. 4, steps (a)-(c); Ex 7

  (WO 2005063705) 19 4-Cyano-1H-imidazole-2- carboxylic acid [4-(1,1-dioxo-1λ⁶- [1,2,6]thiadiazinan-4-yl)- 2-(4-ethyl-cyclohex-1-enyl)-phenyl]-amide

Ex. 4, steps (a)-(b); Ex 5

  (WO 2005063705) 20 4-Cyano-1H-imidazole-2- carboxylic acid [4-(2,6-dimethyl-1,1-dioxo-1λ⁶- [1,2,6]thiadiazinan-4-yl)-2-spiro[4.5]dec-7-en-8-yl- phenyl]-amide

Ex. 4, steps (a)-(b); Ex 5, steps (a); Ex 11

  (WO 2005063705) 21 4-Cyano-1H-pyrrole-2- carboxylic acid [2-cyclohex-1-enyl-4-(2,6- dimethyl-1,1-dioxo- 1λ⁶[1,2,6]thiadiazinan-4-yl)-phenyl]-amide

Ex 11

  (Canadian J. Chem. 59, 2673 (1981)) 22 4-Cyano-1H-imidazole-2-carboxylic acid [4-(2,6- dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)- 2-spiro[2.5]oct-5-en-6-yl- phenyl]-amide

Ex. 4, steps (a)-(c); Ex 5, steps (a); Ex 11

  (WO 2005063705) 23 4-Chloro-1H-imidazole-2- carboxylic acid [4-(2,6-dioxo-piperidin-4-yl)-2- spiro[3.5]non-6-en-7-yl- phenyl]-amide

Ex. 2

  (WO 2005063705);  

  (Example 44, step (b)) 24 5-Cyano-furan-2- carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)- 4-[1-(2-hydroxy-ethyl)-2,6-dioxo-piperidin-4-yl]- phenyl}-amide

Ex. 15 H₂N(CH₂)₂OH;  

  (Combi-Blocks, Inc.);  

  (WO 2004096795 A2)

Example 25 5-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-methyl-1,1,3,3-tetraoxo-1λ⁶,3λ⁶-[1,3,2]dithiazinan-5-yl)-phenyl]-amide

b) 2-Phenyl-propane-1,3-disulfonic acid

To 2-phenyl-propene-1,3-disulfonic acid (J. Amer. Chem. Soc., 66, 1105-9(1944)) in THF-water (1:1) is added 10 wt % of 5% palladium on carbonand the mixture hydrogenated on a Parr shaker under 15 lb hydrogenpressure until the reaction is complete by thin layer chromatography(TLC). The mixture is filtered (Celite) and concentrated in vacuo toafford the title compound.

c) 2-(4-Nitro-phenyl)-propane-1,3-disulfonic acid

2-Phenyl-propane-1,3-disulfonic acid (as prepared in the previous step)is treated with concentrated H₂SO₄ and fuming HNO₃ according to theprocedure of Example 2, step (a) to afford the title compound.

c) 4-(4-Nitro-phenyl)-[1,2,6]oxadithiane 2,2,6,6-tetraoxide

2-(4-Nitro-phenyl)-propane-1,3-disulfonic acid (as prepared in theprevious step) is treated with POCl₃ as described in Chem. Berichte.,91, 1512-15 (1958) and the title compound is isolated and used in thefollowing step without further purification.

d) 2-(4-Methoxy-benzyl)-5-(4-nitro-phenyl)-[1,3,2]dithiazinane1,1,3,3-tetraoxide

A solution of 4-(4-nitro-phenyl)-[1,2,6]oxadithiane 2,2,6,6-tetraoxide(as prepared in the previous step) is treated with 4-methoxy-benzylamineaccording to the procedure of Example 2, step (c) to afford the titlecompound.

e) 5-(4-Nitro-phenyl)-[1,3,2]dithiazinane 1,1,3,3-tetraoxide

2-(4-Methoxy-benzyl)-5-(4-nitro-phenyl)-[1,3,2]dithiazinane1,1,3,3-tetraoxide (as prepared in the previous step) is treated withceric ammonium nitrate (CAN) according to the procedure of Example 2,step (d) to afford the title compound.

f) 5-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-methyl-1,1,3,3-tetraoxo-1λ⁶,3λ⁶-[1,3,2]dithiazinan-5-yl)-phenyl]-amide

The title compound is prepared from5-(4-nitro-phenyl)-[1,3,2]dithiazinane 1,1,3,3-tetraoxide (as preparedin the previous step) using procedures similar to those found in Example1, steps (i)-(m).

The following compounds are prepared by methods similar to previousexamples and with the corresponding reagents as indicated in the table.

26 4- Methyl-1H-imidazole-2- carboxylic acid [2- cyclohex-1-enyl-4-(2-ethyl-1,1,3,3-tetraoxo- 1λ⁶,3λ⁶-[1,3,2]dithiazinan- 5-yl)-phenyl]-amide

Ex. 25 above, steps (a)-(c), (e)-(f) EtNH2;  

  (Example 28, step (c)) 27 4-Cyano-1H-pyrrole-2- carboxylic acid [2-spiro[5.5]undec-2-en-3-yl- 4-(1,1,3,3-tetraoxo-1λ⁶,3λ⁶-[1,3,2]dithiazinan-5-yl)- phenyl]-amide

Ex. 25 above

  (WO 2005063705);  

  (Canadian J. Chem. 59, 2673 (1981))

Example 28 4-Methyl-1H-imidazole-2-carboxylic acid[4-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

a) 5-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL ofacetonitrile at 0° C. was added triethylamine (NEt₃) (4.00 g, 39.6 mmol)and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed toattain RT then filtered to remove the ppt and the filtrate wasconcentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was usedwithout further purification in the next step. To a solution of1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mLacetonitrile was added SEM-C1 (5.80 g, 35.0 mmol) and the solution wasstirred at 25° C. for 10 h. The solvents were removed by evaporation andto the residue was added 100 mL of 2.5 M NaOH and the mixture wasstirred at 25° C. for 1 h. The reaction mixture was then extracted withether (3×100 mL), dried over Na₂SO₄ and concentrated. The title compoundwas purified by chromatography on silica gel eluting with 75%EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum(ESI, m/z): Calcd. for C₁₀H₂₀N₂O₄Si, 213.1 (M+H). found 213.1.

b)5-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (as preparedin the previous step, 0.320 g, 1.50 mmol) in 5 mL of THF at −78° C. wasadded n-BuLi (0.80 mL, 2 M in cyclohexane) and the mixture was allowedto attain RT and stirred for 30 min. The mixture was cooled to −78° C.and ethyl cyanoformate (0.160 g, 1.65 mmol) was added and the mixtureallowed to stir for 10 h at RT. The reaction was diluted with 15 mL ofEtOAc and washed with NaHCO₃ (2×15 mL) and brine (15 mL). The titlecompound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 0.160g (38%) of a light brown oil: Mass spectrum (ESI, m/z): Calcd. forC₁₃H₂₄N₂O₃Si, 285.2 (M+H). found 284.9.

c)5-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

To a solution of5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (as prepared in the previous step, 0.090 g, 0.32 mmol)in 2 mL of ethyl alcohol (EtOH) at RT was added 0.16 mL of 2N KOH. Themixture was stirred for 1 h and then concentrated and dried under vacuumto afford the title compound as a solid that was used without furtherpurification.

d)[4-(2,6-Diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester

The title compound is prepared fromN-[4-(1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-acetamide (asprepared in Example 5, step (a)) and EtI following the procedure ofExample 11, step (a).

e)[2-Bromo-4-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester

The title compound is prepared from[4-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester (as prepared in the previous step) following theprocedure of Example 11, step (b).

f)4-(2,6-Diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine

The title compound is prepared from[2-bromo-4-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamicacid tert-butyl ester (as prepared in the previous step) and4-methylpiperidine following the literature procedure of Buchwald (Org.Lett., 4, 2885-8 (2002)). The residue obtained is purified by silica gelchromatography with an appropriate solvent mixture. After isolation,removal of the BOC protecting group from the resulting intermediate iscarried out by stirring at RT in TFA-DCM (1:2), monitoring by TLC forcompletion, and then concentration in vacuo.

g) 4-Methyl-1H-imidazole-2-carboxylic acid[4-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide

The title compound is prepared from4-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine(as prepared in the previous step) and5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt (as prepared above in this example, step (c))following the procedure of Example 11, steps (d)-(e).

The following compounds are prepared by methods similar to the previousexample, with or without additional procedures, and with thecorresponding reagents as indicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 294-Cyano-1H-imidazole-2- carboxylic acid [4-(1,3- dimethyl-2-oxo-hexahydro-pyrimidin-5- yl)-2-(4-methyl-piperidin- 1-yl)-phenyl]-amide

Example 7, step (a); Example 4, step (b); Example 7, step (d); Example28, steps (e)-(f)

  (Example 7, step (a)) 30 5-Cyano-furan-2- carboxylic acid [4-(1,3-dimethyl-2-oxo- hexahydro-pyrimidin-5- yl)-2-(4,4-dimethyl-piperidin-1-yl)-phenyl]- amide

Example 29

  (US 2003236247);  

  (WO 2004096795 A2) 31 4-Cyano-1H-pyrrole-2- carboxylic acid [4-(1,3-dimethyl-2-oxo- hexahydro-pyrimidin-5- yl)-2-(4,4-dimethyl-piperidin-1-yl)-phenyl]- amide

Example 29

  (US 2003236247)  

  (Canadian J. Chem. 59, 2673 (1981)) 32 5-Cyano-2H- [1,2,4]triazole-3-carboxylic acid [2-(8-aza- spiro[4.5]dec-8-yl)-4-(1,3- dimethyl-2-oxo-hexahydro-pyrimidin-5- yl)-phenyl]-amide

Example 29

  (J. Med. Chem., 8, 766-76 (1965));  

  (Hecheng Huaxue, 11(4), 351-353 (2003)) 33 4-Cyano-1H-imidazole-2-carboxylic acid [4-(2,6- dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)- 2-(4,4-dimethyl-piperidin-1-yl)-phenyl]-amide

Example 28

  (US 2003236247) 34 4-Hydroxy-1H-imidazole- 2-carboxylic acid {4-(2,6-dimethyl-1,1-dioxo-1λ⁶- [1,2,6]thiadiazinan-4-yl)-2-[4-(2-hydroxy-ethyl)- piperidin-1-yl]-phenyl}- amide

Example 28

  (WO 9811086 A1);  

  Berichte, 58B, 1346-53 (1925)

The following compounds are prepared by methods similar to previousexamples with additional procedures and with the corresponding reagentsas indicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 354-Cyano-1H-imidazole-2- carboxylic acid [4-(2,6-dioxo-piperidin-4-yl)-2- piperidin-1-yl-phenyl]- amide

Example 1, steps (a)-(j); Example 28, step (e); Example 1, steps (l)-(m)

36 4-Cyano-1H-imidazole-2- carboxylic acid [4-(2,6-dioxo-piperidin-4-yl)-2-(4- methyl-piperidin-1-yl)- phenyl]-amide

Example 1, steps (a)-(j); Example 28, step (e); Example 1, steps (l)-(m)37 4-Cyano-1H-pyrrole-2- carboxylic acid [4-(2,6-dioxo-piperidin-4-yl)-2-(4- methyl-piperidin-1-yl)- phenyl]-amide

Example 1, steps (a)-(j); Example 28, step (e); Example 1, steps (l)-(m)

  (Canadian J. Chem. 59, 2673 (1981)) 38 5-Cyano-furan-2- carboxylicacid [2-(4,4- dimethyl-piperidin-1-yl)-4- (1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]- amide

Example 15, (a)-(b); Example 4, (a) and (d); Example 28, step (e);Example 1, steps (l)-(m) MeNH₂;  

  (US 2003236247);  

  (WO 2004096795 A2) 39 5-Cyano-1H-imidazole-2- carboxylic acid [2-(4-methyl-piperidin-1-yl)-4- (2-methyl-1,1,3,3-tetraoxo-1λ⁶,3λ⁶-[1,3,2]dithiazinan- 5-yl)-phenyl]-amide

Example 25, steps (a)-(d); Example 1, step (i); Example 43, step (c);Example 4, step (d); Example 28, step (e); Example 1, steps (l)-(m)MeNH₂ 40 5-Cyano-4H- [1,2,4]triazole-3- carboxylic acid [2-(8-aza-spiro[4.5]dec-8-yl)-4- (1,1,3,3-tetraoxo-1λ⁶,3λ⁶-[1,3,2]dithiazinan-5-yl)- phenyl]-amide

Example 25, steps (a)-(d); Example 15, step (c); Example 43, step (c);Example 4, steps (a) and (d); Example 28, step (e); Example 1, steps(l)-(m); Example 2, step (d)

  (J. Med. Chem., 8, 766-76 (1965));  

  (Hecheng Huaxue, 11(4), 351-353 (2003))

The following compound is prepared by methods similar to previousexamples with additional procedures and with the corresponding reagentsas indicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 414-Cyano-1H-imidazole-2- carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)- 2′,6′-dioxo-1′,2′,3′,4′,5′,6′- hexahydro-[2,4′]bipyridinyl-5-yl]- amide

Example 2

  (WO 9737979 A1);  

  (Combi-Blocks, Inc.)

The following compound is prepared by methods similar to previousexamples with additional procedures and with the corresponding reagentsas indicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 424-Cyano-1H-imidazole-2- carboxylic acid (4-methyl- 2″,6″-dioxo-3,4,5,6,1″,2″,3″,4″,5″,6″- decahydro-2H- [1,2′;6′,4″]terpyridin-3'-yl)-amide

Example 2, steps (a)-(d) Example 1, steps (i); Example 4, step (a);Example 43; step (h); Example 1, steps (l)-(m)

  (WO 9737979 A1);  

Example 43 4-Cyano-1H-imidazole-2-carboxylic acid[6′-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

a) 2-(5-Nitro-pyridin-2-yl)-propane-1,3-diol

The title compound is prepared from 2-pyridin-2-yl-propane-1,3-diol(Tetrahedron: Asymmetry 8(13), 2175-2187 (1997)) according to theprocedure in Example 2, step (a).

b) 2-(5-Amino-pyridin-2-yl)-propane-1,3-diol

The title compound is prepared from2-(5-nitro-pyridin-2-yl)-propane-1,3-diol (as prepared in the previousstep) according to the procedure in Example 1, step (i).

c) [6-(2-Hydroxy-1-hydroxymethyl-ethyl)-pyridin-3-yl]-carbamic acidtert-butyl ester

The title compound is prepared from2-(5-amino-pyridin-2-yl)-propane-1,3-diol (as prepared in the previousstep) and (BOC)₂O according to standard procedures found in “ProtectiveGroups in Organic Synthesis”, by Theodora W. Greene and Peter G. M.Wuts, John Wiley & Sons, Inc. NY, (1999).

d) [6-(2-Amino-1-aminomethyl-ethyl)-pyridin-3-yl]-carbamic acidtert-butyl ester

The title compound is prepared from[6-(2-hydroxy-1-hydroxymethyl-ethyl)-pyridin-3-yl]-carbamic acidtert-butyl ester (as prepared in the previous step) according to theprocedure in Example 4, step (b).

e) [6-(2-Oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamic acidtert-butyl ester

The title compound is prepared from[6-(2-amino-1-aminomethyl-ethyl)-pyridin-3-yl]-carbamic acid tert-butylester (as prepared in the previous step) according to the procedure inExample 4, step (c).

f)[6-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamicacid tert-butyl ester

The title compound is prepared from[6-(2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamic acidtert-butyl ester (as prepared in the previous step) according to theprocedure in Example 7, step (a).

g)[2-Bromo-6-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamicacid tert-butyl ester

The title compound is prepared from[6-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamicacid tert-butyl ester (as prepared in the previous step) according theprocedure in Example 4, step (d).

h)5-(3′-Amino-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one

The title compound is prepared from[2-bromo-6-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamicacid tert-butyl ester (as prepared in the previous step) and4,4-dimethylpiperidine (US 2003236247) following the literatureprocedure of Buchwald (Org. Lett., 4, 2885-8 (2002)). The residueobtained is purified by silica gel chromatography with an appropriatesolvent mixture. After isolation, removal of the BOC protecting groupfrom the resulting intermediate is carried out by stirring at RT inTFA-DCM (1:2), monitoring by TLC for completion, and then concentrationin vacuo.

i) 4-Cyano-1H-imidazole-2-carboxylic acid[6′-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

The title compound is prepared from5-(3′-amino-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one(as prepared in the previous step) according to the procedures inExample 1, steps (1) and (m).

Example 44 4-Chloro-1H-imidazole-2-carboxylic acid[6′-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

a)4-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

The title compound was prepared according to the procedure of Example51, step (b) substituting N-chlorosuccinimide (NCS) for NBS. Massspectrum (ESI, m/z): Calcd. for C₁₂H₂₁ClN₂O₃Si, 305.1 (M+H). found304.7.

b)4-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

The title compound was prepared from4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (prepared in the previous step) according to theprocedure in Example 1, step (d). Mass spectrum (ESI, m/z): Calcd. forC₁₀H₁₆ClKN₂O₃Si, 277.1 (M+H−K). found 276.7.

c)6′-(2,6-Diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine

The title compound is prepared from4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (prepared in the previous step) according to theprocedure in Example 1, steps (a)-(h) substituting EtI for Me₂SO₄.

d) 4-Chloro-1H-imidazole-2-carboxylic acid[6′-(2,6-diethyl-1,1-dioxo-1⁶-[1,2,6]thiadiazinan-4-yl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-amide

The title compound is prepared from6′-(2,6-diethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-yl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-3′-ylamine(as prepared in the previous step) and4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in this example, step (b) following theprocedure of Example 1, step (1)) followed by the procedure of Example1, step (m).

The following compounds are prepared by methods similar to the previousexample with the corresponding reagents as indicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 454-Cyano-1H-imidazole-2- carboxylic acid [6′-(1,3- dimethyl-2-oxo-hexahydro-pyrimidin-5- yl)-4,4-dimethyl- 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]- amide

Example 44

  (US 2003236247);  

  (Example 1, step (d) 46 5-Cyano-2H- [1,2,4]triazole-3- carboxylic acid[6′-(2,6- dimethyl-1,1-dioxo-1λ⁶- [1,2,6]thiadiazinan-4-yl)-4-methyl-3,4,5,6- tetrahydro-2H- [1,2′]bipyridinyl-3′-yl]- amide

Example 44

  (Hecheng Huaxue, 11(4), 351-353 (2003))

The following compounds are prepared by methods similar to the previousexamples with modifications and with the corresponding reagents asindicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 474-Cyano-1H-imidazole-2- carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)- 6-(1,3-dimethyl-2-oxo- hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-amide

Example 43, steps (a)- (g); Example 3, step (a) and (c); Example 1, step(l)-(m)

  (Combi-Blocks, Inc.) 48 5-Cyano-furan-2- carboxylic acid [6-(1,3-dimethyl-2-oxo- hexahydro-pyrimidin-5- yl)-2-spiro[4.5]dec-7-en-8-yl-pyridin-3-yl]-amide

Example 43, steps (a)- (g); Example 3, step (a) and (c); Example 1, step(l)-(m)

  (WO 2005063705);  

  (WO 2004096795 A2) 49 4-Cyano-1H-pyrrole-2- carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)- 6-(2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4- yl)-pyridin-3-yl]-amide

Example 43, steps (a)-(d); Example 5, step (a); Example 11, steps(a)-(d)

  (Combi-Blocks, Inc.)  

  (Canadian J. Chem. 59, 2673 (1981)) 50 4-Cyano-1H-imidazole-2-carboxylic acid [2-(4,4- dimethyl-cyclohex-1-enyl)-6-(2,6-dimethyl-1,1-dioxo- 1λ⁶-[1,2,6]thiadiazinan-4-yl)-pyridin-3-yl]-amide

Example 43, steps (a)-(d); Example 5, step (a); Example 11, steps(a)-(e)

  (Combi-Blocks, Inc.)

Example 51{5-[4-[(4-Bromo-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyrimidin-2-ylidene}-carbamicacid methyl ester

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acidethyl ester

A flask charged with 1H-imidazole-2-carboxylic acid ethyl ester (1.03 g,7.36 mmol), K₂CO₃ (2.00 g, 14.5 mmol), SEM-C1 (1.56 mL, 8.89 mmol), and20 mL of acetone was stirred for 10 h at RT. The reaction was dilutedwith EtOAc (100 mL), washed with NaHCO₃ (2×100 mL), brine (100 mL), andthe organic layer dried over Na₂SO₄ and concentrated. The title compoundwas eluted from a 20-g SPE with 50% EtOAc/hexanes to give 1.50 g (76%)of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C₁₂H₂₂N₃O₃Si,271.1 (M+H). found 271.1.

b) 4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethylester (0.20 g, 0.74 mmol) (prepared in the previous step) in 2 mL ofCH₃CN was added NBS (0.13 g, 0.74 mmol) and the mixture heated to 60° C.for 2 h. The mixture was concentrated and the title compound purified byelution from a 20-g SPE column with 20% EtOAc/hexanes to give 0.10 g(39%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. forC₁₂H₂₁BrN₂O₃Si, 349.0 (M+H). found 348.7.

c)4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

The title compound was prepared according to the procedure in Example 1,step (d). Mass spectrum (ESI, m/z): Calcd. for C₁₀H₁₆BrKN₂O₃Si, 322.0(M+H−K). found 322.6.

d){5-[4-[(4-Bromo-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyrimidin-2-ylidene}-carbamicacid methyl ester

The title compound is prepared according to the procedures in Example 12substituting4-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in this example, step (c)) for4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt and substituting 4,4-dimethyl-cyclohex-1-enylboronic acidfor cyclohex-1-enylboronic acid.

Examples 52 and 53 are prepared by methods similar to the previousexample with the corresponding reagents as indicated in the table.

Proce- Ex- dure ample Refer- No. Name Structure ence Reagents 524-Cyano-1H-imidazole-2- carboxylic acid [4-(2- nitroimino-hexahydro-pyrimidin-5-yl)-2-(4,4- dimethyl-cyclohex-1-enyl)- phenyl]-amide

Example 51

  (Combi-Blocks, Inc.);  

  (Aldrich Chemical Co., Inc.);  

  (Example 1, step (d) 53 {5-[4-[(4-Cyano-1H- imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl- cyclohex-1-enyl)-phenyl]-tetrahydro-pyrimidin-2- ylidene}-carbamic acid methyl ester

Example 51

  (Combi-Blocks, Inc.);  

  (Helv. Chim. Acta, 35, 1005- (Example 1, step (d) 20 (1952));  

  (Example 1, step (d)

Example 54 4-Cyano-1H-imidazole-2-carboxylic acid[4-(2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amidetrifluoroacetic acid salt

a.) 5-(4-Bromo-phenyl)-tetrahydro-pyrimidin-2-ylidene-cyanamide

To a stirred suspension of 2-(4-bromo-phenyl)-propane-1,3-diol (462 mg,2.00 mmol, JACS, 125(46), 13948) in DCM (50 mL) and Et₃N (0.7 mL, 5mmol) was added MsCl (0.3 mL, 4.0 mmol) at 0° C. The resulting mixturewas allowed to warm to RT and stirred for 4 h and treated with satdNaHCO₃ (50 mL). The DCM layer was separated and the aq layer wasextracted twice with DCM (2×20 mL). The organic layers were combined,dried (Na₂SO₄) and concentrated in vacuo. The resulting bismesylate wasdried under high vacuum for 2 h and redissolved in DMF (5 mL) To thismixture NaN₃ (0.52 g, 8.0 mmol) was added. The resulting mixture washeated at 70° C. over night. The reaction mixture was allowed to cool toRT and treated with water (10 mL). The product was then extracted withEtOAc (3×10 mL). The organic layers were combined, dried (Na₂SO₄) andconcentrated in vacuo. The resulting diazide was dried under high vacuumfor 2 h and used in next step without further purification. The diazide(280 mg, 1 mmol) was dissolved in MeOH (5 mL) and Et₃N (1.4 mL, 10 mmol)and the resulting solution was placed under N₂. To this solutionpropanedithiol (1.0 mL, 10 mmol) was added. The resulting mixture wasstirred at RT overnight and concentrated to obtain a viscous oil whichwas dried under high vacuum for 2 h, dissolved in ether (20 mL) andtreated with 2M HCl in ether (10 mL, 20 mmol). The resulting suspensionwas sonicated for 5 min and stirred for 5 h. The precipitate formed wascollected by suction filtration and dried in vacuo to obtain2-(4-bromo-phenyl)-propane-1,3-diamine dihydrochloride which wasdirectly used in next step without further purification. Thedihydrochloride salt (302 mg, 1 mmol) was added to a solution of Et₃N(0.7 mL, 5 mmol) and dimethyl N-cyanodithioiminocarbonate (146 mg, 1.00mmol) in EtOH (10 mL). The resulting mixture was heated at 80° C.overnight. The reaction mixture was allowed to cool to RT and stirredfor another 2 h. The precipitate formed was collected by suctionfiltration to obtain 92 mg (33%) of the title compound. Mass spectrum(ESI, m/z): Calcd. for C₁₁H₁₁BrN₄, 279.0 (M+H). found 279.1.

b)5-(4-Bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

To a suspension of NaH (80 mg, 2 mmol) in dry DMF (10 mL),5-(4-bromo-phenyl)-tetrahydro-pyrimidin-2-ylidene-cyanamide (279 mg,1.00 mmol, as prepared in the previous step) in DMF (5 mL) was addeddropwise at 0° C. The resulting mixture was stirred at RT for 30 min andcooled back to 0° C. and treated with MeI (0.24 mL, 4.0 mmol). Themixture was allowed to warm to RT, stirred for 2 h and diluted withwater (10 mL) and extracted with DCM (3×20 mL). The DCM layers werecombined, dried (Na₂SO₄) and concentrated. The solid obtained wassuspended in hexane and sonicated for 5 min and the precipitate wascollected by suction filtration 173 mg, 62%. Mass spectrum (ESI, m/z):Calcd. for C₁₃H₁₅BrN₄, 307.0 (M+H). found 307.4.

c)5-(4-Amino-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

To a screw-capped vial containing tri-tert-butylphosphine (5.0 mg, 0.025mmol), Pd₂(dba)₃ (14.3 mg, 0.0250 mmol), Zn[N(SiMe₃)₂]₂ (116 mg, 0.300mmol) and LiCl (12.6 mg, 0.300 mmol) under Ar was added5-(4-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide(153 mg, 0.500 mmol), as prepared in the previous step) in THF (1 mL).The reaction mixture was then stirred at 60° C. overnight and allowed tocool to RT and treated with 1 N HCl (0.2 mL). The reaction mixture wasthen transferred to a reparatory funnel, diluted with DCM (10 mL) andwashed with 1N NaOH (5 mL). The DCM layers were combined, dried (Na₂SO₄)and concentrated. The solid obtained was purified on silica (50%-100%EtOAc/hexane) to obtain 40 mg, 33% of the title compound. Mass spectrum(ESI, m/z): Calcd. for C₁₃H₁₇N₅, 244.10 (M+H). found 244.2.

d)5-(4-Amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

The title compound was prepared according to the bromination procedureof Example 1, step (j), using5-(4-amino-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamideas the starting material: Mass spectrum (ESI, m/z): Calcd. forC₁₃H₁₆BrN₅, 322.1 (M+H). found 322.2.

e)5-[4-Amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

The title compound was prepared according to the Suzuki couplingprocedure of Example 3, step (a), using 4,4-dimethyl-cyclohex-1-enylboronic acid and5-(4-amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamideMass spectrum (ESI, m/z): Calcd. for C₂₁H₂₉N₅, 352.2 (M+H). found 352.4

f) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[4-(2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide

5-[4-Amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide(as prepared in the previous step) was coupled to4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 1) as described in Example1, step (1) to obtain the title compound: Mass spectrum (ESI, m/z):Calcd. for C₃₂H₄₄N₈O₂Si, 601.3 (M+H). found 601.3.

g) 4-Cyano-1H-imidazole-2-carboxylic acid[4-(2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amidetrifluoroacetic acid salt

The title compound was synthesized from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[4-(2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide(as prepared in the previous step) as described in Example 7, step (e):¹H-NMR (CD₃OD; 400 MHz): δ 8.22 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.25(dd, 1H, J=8.4, 2.1 Hz), 7.08 (d, 1H, J=2.1 Hz), 5.82 (br s, 1H),3.4-3.6 (m, 4H), 3.25 (s, 6H), 3.1-3.2 (m, 1H), 2.38 (m, 2H), 2.15 (m,2H), 1.62 (m, 2H), 1.15 (s, 6H); Mass spectrum (ESI, m/z): Calcd. forC₂₆H₃₀N₈O, 471.2 (M+H). found 471.3.

IV. Results

Fluorescence Polarization Competition Immunoassay

A fluorescence polarization competition immunoassay was used to measurecompound inhibition of CSF-1R phosphorylation of tyrosine on a syntheticCSF-1R₅₅₅₋₅₆₈ peptide (SYEGNSYTFIDPTQ). The assay was performed in black96-well microplates (Cat #42-000-0117, Molecular Devices, Sunnyvale,Calif.). To each well, 5 μL of compound (in 4% DMSO) were mixed with 2μL of 3.5 nM CSF-1R, 25 mM MgCl₂ in assay buffer (100 mM HEPES, pH 7.5,1 mM DTT, 0.01% Tween-20), and 2 μL of 1540 μM peptide in assay buffer.The kinase reaction was initiated by adding 1 μL of 10 mM ATP in assaybuffer. The final concentrations in the 10 uL reaction mixture were 100mM HEPES, pH 7.5, 1 mM DTT, 0.01% Tween-20, 2% DMSO, 308 μMSYEGNSYTFIDPTQ, 1 mM ATP, 5 mM MgCl₂, and 0.7 nM CSF-1R. Positive andnegative control wells were included on each plate, where 4% DMSO inassay buffer was substituted for the compound; in addition, positivecontrol wells received 1.2 μL of 50 mM EDTA before the start of thereaction.

The plates were covered and incubated at room temperature for 80 min.Reactions were stopped by addition of 1.2 μL of 50 mM EDTA. Each wellthen received 10 μL of a 1:1:3 mixture of 10× anti-phosphotyrosineantibody, 10×PTK green tracer, and FP dilution buffer, respectively(Cat. #P2837, Invitrogen, Carlsbad, Calif.). The plates were covered,incubated for 30 min at room temperature, and the fluorescencepolarization was read on an Analyst plate reader (Molecular Devices).Instrument settings were: 485 nm excitation, 530 nm emission, with a 505nm cut-off filter; Z height: middle of well; G factor: 0.93. Under theseconditions, the fluorescence polarization values for positive andnegative controls were approximately 290 and 160, respectively, and wereused to define 100% and 0% inhibition of the CSF-1R reaction. ReportedIC₅₀ values are the mean of three of at least three determinations.

CSF-1-Driven Mouse Bone-Marrow Derived Macrophages Assay

Macrophages are derived by culturing mouse bone marrow in alpha-MEMsupplemented with 10% FCS (fetal calf serum) and 50 ng/ml recombinantmouse CSF-1 in bacteriologic dishes. On the sixth day, macrophages aredetached from dishes, washed, and resuspended to 0.1 million cells/ml inalpha-MEM containing 10% FCS. One hundred ul of cell suspension aredistributed per well into 96 well culture plates. Wells are furthersupplemented with the addition of 50 ul media containing 15 ng/ml CSF-1,3 uM Indomethacin, and 3× of a dilution series of test compounds. Thecells are cultured for 30 hrs at 37° C. and 5% CO₂. During the final sixhours, cultures are supplemented with an additional 30 ul of mediacontaining a 1:500 dilution of bromodeoxyuridine (BrDU). At the end ofthe culture period, the media is removed and replaced with 200 offixative solution for 30′ @ room temperature. The fixative is thendispelled from the plates and the plates allowed to air dry.Incorporation of BrDU into the fixed, dried cells is quantified using aspecific ELISA (Cat X1327K) from Exalpha Corporation (Watertown Mass.).Background values are determined from wells without BrDU reagent. IC50values are calculated based on signal from CSF-1 stimulated cellswithout compound present.

Table 1 lists the assay results for representative compounds of theinvention.

TABLE 1 mCSF driven Example IC50 proliferation BMDM Number (μM) (Mouse)(μM) 1 0.001 0.01 3 0.001 0.007 4 0.003 0.07 5 0.003 0.06 6 0.01 0.06 70.001 0.01 8 0.0004 0.003 9 0.001 0.005 10 N/A 0.1 11 0.002 0.002 120.003 0.04 13 0.002 0.1 14 0.001 0.004 15 >0.3 N/A 54 0.00042 0.039

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

All publications disclosed in the above specification are herebyincorporated by reference in full.

1-23. (canceled)
 24. A method of inhibiting inflammation, treating pain,or treating metastasis in mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of atleast one compound of formula I:

wherein: W is

wherein R⁴=H, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, —C₍₁₋₃₎alkyl, —CO₂R⁵,CONR⁶R⁷, C≡CR⁸, or CN; wherein R⁵=H, or —C₍₁₋₃₎alkyl; R⁶=H, or—C₍₁₋₃₎alkyl; R⁷=H, or —C₍₁₋₃₎alkyl; and R⁸=H, —CH₂OH, or —CH₂CH₂OH; R²is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl,spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl,phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which maybe independently substituted with one or two of each of the following:chloro, fluoro, hydroxy C₍₁₋₃₎alkyl, and C₍₁₋₄₎alkyl; X is selected fromthe group consisting of:

wherein R¹ and R¹⁰ are independently H, —CH₃, or —C₂-C₅ alkyl,optionally substituted with one or two of: Me, Et, OH, NH₂, NHMe, NMe₂,NHEt, NEt₂, pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH and suchthat when any two heteroatoms are attached to said C₂ to C₅ alkyl groupthere exists at least two carbon atoms between them, and Z is H, F, Cl,Br, C₁-C₃ alkyl or —CH₂OH; and J is CH or N; or a tautomer orpharmaceutically acceptable salt thereof.
 25. The method of claim 24,which comprises inhibiting inflammation.
 26. The method of claim 25,wherein the inflammation is a component of a disease selected from thegroup consisting of glomerulonephritis, inflammatory bowel disease,prosthesis failure, sarcoidosis, congestive obstructive pulmonarydisease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIVinfection, psoriasis, diabetes, tumor related angiogenesis, age-relatedmacular degeneration, diabetic retinopathy, restenosis, schizophreniaand Alzheimer's dementia.
 27. The method of claim 24, which comprisestreating pain.
 28. The method of claim 27, wherein the pain is selectedfrom the group consisting of skeletal pain caused by tumor metastasis orosteoarthritis, visceral, inflammatory, and neurogenic pain.
 29. Themethod of claim 24, which comprises treating metastasis.
 30. The methodof claim 29, wherein the metastasis is from ovarian cancer, uterinecancer, breast cancer, prostate cancer, lung cancer, colon cancer,stomach cancer, and hairy cell leukemia.
 31. A method of treatingosteoporosis, Paget's disease, and other diseases in which boneresorption mediates morbidity including rheumatoid arthritis, and otherforms of inflammatory arthritis, osteoarthritis, prosthesis failure,osteolytic sarcoma, myeloma, and tumor metastasis to bone, comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of at least one compound of formula I:

wherein: W is

wherein R⁴=H, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, —C₍₁₋₃₎alkyl, —CO₂R⁵,CONR⁶R⁷, C≡CR⁸, or CN; wherein R⁵=H, or —C₍₁₋₃₎alkyl; R⁶=H, or—C₍₁₋₃₎alkyl; R⁷=H, or —C₍₁₋₃₎alkyl; and R⁸=H, —CH₂OH, or —CH₂CH₂OH; R²is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl,spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl,phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which maybe independently substituted with one or two of each of the following:chloro, fluoro, hydroxy C₍₁₋₃₎alkyl, and C₍₁₋₄₎alkyl; X is selected fromthe group consisting of:

wherein R¹ and R¹⁰ are independently H, —CH₃, or —C₂-C₅ alkyl,optionally substituted with one or two of: Me, Et, OH, NH₂, NHMe, NMe₂,NHEt, NEt₂, pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH and suchthat when any two heteroatoms are attached to said C₂ to C₅ alkyl groupthere exists at least two carbon atoms between them, and Z is H, F, Cl,Br, C₁-C₃ alkyl or —CH₂OH; and J is CH or N; or a tautomer orpharmaceutically acceptable salt thereof.
 32. A method of treating anautoimmune disease selected from the group consisting of systemic lupuserythematosus, rheumatoid arthritis, and other forms of inflammatoryarthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, anduveitis in a mammal comprising administering to a mammal in need of suchtreatment a therapeutically effective amount of at least one compound offormula I:

wherein: W is

wherein R⁴=H, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, —C₍₁₋₃₎alkyl, —CO₂R⁵,CONR⁶R⁷, C≡CR⁸, or CN; wherein R⁵=H, or —C₍₁₋₃₎alkyl; R⁶=H, or—C₍₁₋₃₎alkyl; R⁷=H, or —C₍₁₋₃₎alkyl; and R⁸=H, —CH₂OH, or —CH₂CH₂OH; R²is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl,spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl,phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which maybe independently substituted with one or two of each of the following:chloro, fluoro, hydroxy C₍₁₋₃₎alkyl, and C₍₁₋₄₎alkyl; X is selected fromthe group consisting of:

wherein R¹ and R¹⁰ are independently H, —CH₃, or —C₂-C₅ alkyl,optionally substituted with one or two of: Me, Et, OH, NH₂, NHMe, NMe₂,NHEt, NEt₂, pyrrolidinyl, pyridyl, morpholino, CONH₂, or COOH and suchthat when any two heteroatoms are attached to said C₂ to C₅ alkyl groupthere exists at least two carbon atoms between them, and Z is H, F, Cl,Br, C₁-C₃ alkyl or —CH₂OH; and J is CH or N; or a tautomer orpharmaceutically acceptable salt thereof.